WO2021106988A1

WO2021106988A1 - G9a INHIBITOR

Info

Publication number: WO2021106988A1
Application number: PCT/JP2020/043966
Authority: WO
Inventors: 龍展角谷; 洋輔西ヶ谷; 亮介浪江; 橋本　憲明; 昭博伊藤; 文幸白井; 貢喜久里; 吉田　稔
Original assignee: 杏林製薬株式会社; 国立研究開発法人理化学研究所; 学校法人東京薬科大学; 公益財団法人微生物化学研究会
Priority date: 2019-11-27
Filing date: 2020-11-26
Publication date: 2021-06-03
Also published as: EP4066896A4; EP4066896A1; JPWO2021106988A1; CA3163206A1; US20230127046A1

Abstract

It was found that a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof has potent G9a inhibitory activity. Because of the ability to inhibit G9a, the compound (I) or a pharmaceutically acceptable salt thereof is highly useful in treatment, prevention or suppression of a variety of diseases (including proliferative diseases such as cancer, β-globin abnormalities, fibrosis, pain, neurodegenerative diseases, Prader-Willi syndrome, malaria, viral infections, myopathy, and autism).

Description

G9a inhibitor

The present invention relates to a derivative having a histone methyltransferase G9a inhibitory action useful as a pharmaceutical product, or a pharmacologically acceptable salt thereof, a pharmaceutical composition containing the same, and its pharmaceutical use.

Lysine methylation of histones is a biochemical reaction in which S-adenosylmethionine (SAM) is used as a methyl group donor to add a methyl group to the ε-amino group of a lysine residue of histones. Histone lysine methylation plays an important role in transcriptional regulation and is important in various biological processes including cell proliferation and cell differentiation. As an enzyme that catalyzes the lysine methylation reaction of histones, histone methyltransferase (also referred to as lysinemethyltransferase) is known (Non-Patent Document 1).

G9a and GLP (G9a like protein) are the major enzymes that catalyze the mono and dimethylation (H3K9me1 and H3K9me2) of the 9th lysine residue of histone H3. Also known as EHMT2 and EHMT1 (euchromatin histone-lysine N-methyltransferases 2 and 1).

H3K9me2 is an epigenetic mark related to transcriptional repression. G9a and GLP are involved in epigenetic transcriptional repression by H3K9me2.

Therefore, inhibition of G9a is considered to be useful for controlling cell proliferation and cell differentiation, which are biological processes mediated by transcriptional repression by H3K9me2. Diseases for which G9a inhibitors may be effective include β-globin disorders such as sickle cell disease, gastric cancer, hepatocellular carcinoma, leukemia such as acute myelogenous leukemia and chronic myelogenous leukemia, and cervix. Leukemia, glioma, pancreatic cancer, colon cancer, head and neck squamous epithelial cancer, breast cancer, lung cancer, ovarian cancer, melanoma, fibrosis such as pulmonary fibrosis and renal fibrosis, pain, Alzheimer's disease Neurodegenerative diseases such as diseases, plada-willy syndrome, malaria, mouth-foot disease, viral infections such as bullous stomatitis, myeloid disease, myopathy, autism and the like can be mentioned. Furthermore, it has been suggested that inhibition of G9a may also be effective in suppressing cancer metastasis. In addition, inhibition of G9a has been shown to be effective for sex reversal (Non-Patent Documents 1-24).

Examples of the compound having G9a inhibitory activity include BIX-01294 (Patent Document 1), quinazolines (Patent Document 2), 2-aminoindoles (Patent Document 3), heteroaryls (Patent Document 4), and tricyclic compounds. (Patent Document 5) and the like are known, but the structure is different from that of the compound of the present invention.

International Release 2012/023285 International Publication 2013/140148 US2015274660 Japanese Unexamined Patent Publication No. 2019-513778 Japanese Unexamined Patent Publication No. 2019-511472

The present invention has been made in view of the above-mentioned problems of the prior art, has excellent G9a inhibitory activity, is useful for the treatment of β-globin disorders such as sickle cell disease, and others. Compounds useful for the treatment of proliferative diseases such as sickle cells, fibrosis, pain, neurodegenerative diseases, Prader Willy syndrome, malaria, viral infections, myopathy, autism, etc. and their pharmacologically acceptable salts , And G9a inhibitors and pharmaceutical compositions containing them. Furthermore, it is an object of the present invention to provide a method for producing the compound and a pharmacologically acceptable salt thereof, and an intermediate compound useful for the production thereof.

At present, as a preventive and therapeutic agent for the above-mentioned various pathological conditions, no compound having an excellent G9a inhibitory action and capable of being a sufficiently satisfactory drug has been found.
An object of the present invention is to provide a compound having a G9a inhibitory action.

As a result of diligent research, the present inventors have found that a compound represented by the following general formula (I) (hereinafter, may be referred to as compound (I)) or a pharmacologically acceptable salt thereof inhibits G9a. The present invention has been completed by finding that it has an action and is sufficiently satisfactory as a pharmaceutical.

That is, the present invention is as follows.

[1] General formula (I):

[In formula (I), R ¹ is an oxygen atom, a nitrogen atom or a hydrogen atom;
When R ¹ is an oxygen atom or a nitrogen atom, ^{the bond between R 1} and the carbon atom is a double bond;
If R ¹ is a hydrogen atom, ^{the bond between R 1} and the carbon atom is a single bond;
R ² is the following A1), A2) is or A3), * represents a binding position to -CO- in formula (I);

E is an oxygen atom or a hydrogen atom;
If E is an oxygen atom, the bond between E and the carbon atom is a double bond;
If E is a hydrogen atom, the bond between E and the carbon atom is a single bond;
R ^2a , R ^2b and R ^2c are independently hydrogen atoms, C ₁ to C ₆ alkyl groups, C ₂ to C ₆ alkenyl groups, halo C ₁ to C ₆ alkyl groups, C ₁ to C ₆ alkoxy groups, C. ₁ to C ₆ alkylamino group, C ₁ to C ₆ acyl group, C ₁ to C ₆ alkoxycarbonyl group, C ₃ to C ₁₀ cycloalkyl group or hydroxy C ₁ to C ₆ alkyl group (the C ₁ to C ₆ alkyl) _group, C 2 ~ _{C 6} alkenyl group, halo _C 1 ~ _{C 6} alkyl _group, C 1 ~ _{C 6} alkoxy _group, C 1 ~ _{C 6} alkylamino _group, C 1 ~ _{C 6} acyl _group, C 1 ~ _{C 6} alkoxy The carbonyl group, C ₃ to C ₁₀ cycloalkyl group and hydroxy C ₁ to C ₆ alkyl group are C ₁ to C ₆ alkyl group, C ₁ to C ₆ alkoxy group, C ₁ to C ₆ alkyl amino group and hydroxy C ₁ to it may be one or more substituted with substituents selected from the group consisting of C ₆ alkyl group, a linked together with another substituent may form a ring);
R ^2b and R ^2c may combine with each other to form a ring;
R ^2d and R ^2e are independently C ₁ to C ₆ alkyl groups or hydroxy C ₁ to C ₆ alkyl groups;
R ^2d and R ^2e may be coupled to each other to form a ring;
R ⁶ and R ⁷ are independently hydrogen atoms, C ₁ to C ₆ alkyl groups, aromatic hydrocarbon ring groups, C ₃ to C ₁₀ cycloalkyl groups, 5 to 10 member heteroaryl groups or 3 to 10 member hetero. It is a cycloalkyl group;
R ⁶ and R ⁷ may combine with each other to form a ring;
n is 0 or 1;
RingA is an aromatic hydrocarbon ring group, a C ₃ to C ₁₀ cycloalkyl group, a 5 to 10 member heteroaryl group or a 3 to 10 member heterocycloalkyl group, which ^{may be substituted with R 8} and R ^{9, respectively.} ;
R ⁸ is a hydrogen atom, a halogen atom, a cyano group, an amino group, an aminosulfonyl group (-SO ₂ NH ₂ ), a C ₁ to C ₆ alkyl group, a halo C ₁ to C ₆ alkyl group or a C ₁ to C ₆ alkoxy group. Is;
R ⁹ is -YZ;
Y is the bond, -O-, -NR ^10- or-(CR ¹¹ R ¹² ) _s- ;
R ¹⁰ , R ¹¹ and R ¹² are independent hydrogen atoms or C ₁ to C ₆ alkyl groups, respectively;
s is an integer from 0 to 6;
Z is a hydrogen atom, C ₁ to C ₆ alkyl group, halo C ₁ to C ₆ alkyl group, C ₁ to C ₆ alkoxy group, C ₁ to C ₆ alkyl amino group, aromatic hydrocarbon ring group, C ₃ to. C ₁₀ cycloalkyl group, 5 to 10 member heteroaryl group or 3 to 10 member heterocycloalkyl group (the C ₁ to C ₆ alkyl group, aromatic hydrocarbon ring group, C ₃ to C ₁₀ cycloalkyl group, 5 to The 10-membered heteroaryl group and the 3- to 10-membered heterocycloalkyl group are C ₁ to C ₆ alkyl groups, halo C ₁ to C ₆ alkyl groups, C ₁ to C ₆ alkoxy groups, C ₁ to C ₆ alkyl amino groups, It may be substituted with one or more substituents selected from the group consisting of C ₁ to C ₆ acyl groups and C ₁ to C _{6 alkoxycarbonyl groups);}
R ³ is *-(CH ₂ ) _x- T- (CR ¹³ R ¹⁴ ) _y- U, and * indicates the binding position with -CH- in formula (I);
T is binding, -NH-, -O- or -S (O) _p- ;
U is hydrogen atom, C 3 _~ C ₁₀ cycloalkyl group or an aromatic hydrocarbon Hajime Tamaki (the aromatic hydrocarbon ring group may be one or more substituted with halogen atom);
R ¹³ and R ¹⁴ are independent hydrogen atoms or C ₁ to C ₆ alkyl groups, respectively;
x and y are independently integers from 0 to 4;
p is an integer between 0 and 2;
R ⁴ is a hydrogen atom or a C ₁ to C ₆ alkyl group;
R ⁵ is the following B1) or C ₁ to C ₆ alkyl group, where * indicates the bonding position with -N- in formula (I);

R ¹⁵ and R ¹⁶ are independently hydrogen atoms, C ₁ to C ₆ alkyl groups or hydroxy C ₁ to C ₆ alkyl groups;
R ¹⁵ and R ¹⁶ may combine with each other to form a ring;
R ¹⁵ and R ¹⁶ may combine with Ring B to form a ring;
m is 0 or 1;
^{RingB may be substituted with R 17} , R ¹⁸ and R ¹⁹ , respectively, aromatic hydrocarbon ring groups, C ₃ to C ₁₀ cycloalkyl groups, 5 to 10 member heteroaryl groups or 3 to 10 member heterocycloalkyl groups. Is the basis;
R ¹⁷ and R ¹⁸ are independently hydrogen atom, halogen atom, hydroxyl group, amino group, cyano group, carbamoyl group (-CONH ₂ ), C ₁ to C ₆ alkyl group, halo C ₁ to C ₆ alkyl group, hydroxy. C ₁ to C ₆ alkyl groups, C ₁ to C ₆ alkoxy groups, C ₁ to C ₆ alkyl amino groups, C ₁ to C ₆ alkyl sulfanyl groups, halo C ₁ to C ₆ alkyl sulfanyl groups, C ₁ to C ₆ acyls Group, C ₁ to C ₆ alkoxycarbonyl group, C ₁ to C ₆ alkylaminocarbonyl group or C ₁ to C ₆ acylamino group;
R ¹⁹ is-(CR ²⁰ R ²¹ ) _r- V- (CR ²² R ²³ ) _q- Q;
V is a bond, -O-, -NR ^24- or -S (O) _t- ;
t is an integer between 0 and 2;
R ²⁰ , R ²¹ , R ²² , R ²³ and R ²⁴ are independently hydrogen atoms or C ₁ to C ₆ alkyl groups;
q and r are independently integers from 0 to 6;
Q is a hydrogen atom, an amino group, a hydroxyl group, a C ₁ to C ₆ alkyl group, a C ₁ to C ₆ alkyl amino group, a C ₃ to C ₁₀ cycloalkyl group, a 5 to 10 member heteroaryl group or a 3 to 10 member heterocyclo. Alkyl groups (the C ₁ to C ₆ alkylamino groups, C ₃ to C ₁₀ cycloalkyl groups, 5 to 10 member heteroaryl groups and 3 to 10 member heterocycloalkyl groups are halogen atoms, C ₁ to C ₆ alkyl groups. , C ₁ to C ₆ alkoxy groups, C ₁ to C ₆ alkylamino groups, C ₁ to C ₆ alkoxycarbonyl groups, C ₁ to C ₆ alkylaminocarbonyl groups and hydroxy C ₁ to C ₆ alkyl groups. It may be substituted with one or more substituents);
R ¹⁷ , R ¹⁸ and R ¹⁹ may combine with each other to form a ring;
Bonded together R ⁴ and R ⁵ may form a ring;
When R ¹ is a nitrogen atom, m is 0, and Ring B is a phenyl group that may be substituted with ^{R 17} , R ¹⁸ and R ¹⁹ ^{, R 1} and the phenyl group combine to form a benzimidazole ring. May]
A compound represented by, or a pharmacologically acceptable salt thereof.
[2] In formula (I), R ¹ is an oxygen atom, the compound according to [1], or a pharmacologically acceptable salt thereof.
[3] In the formula (I), R ² is the following A1) or A2).

The compound according to [2], or a pharmacologically acceptable salt thereof.
[4] In equation (I), R ² is the following A2);

R ^2a is a C ₁ to C ₆ alkyl group, a C ₃ to C ₁₀ cycloalkyl group or a hydroxy C ₁ to C ₆ alkyl group,
The compound according to [3], or a pharmacologically acceptable salt thereof.
[5] In the formula (I), R ² is the following A2b).

The compound according to [4], or a pharmacologically acceptable salt thereof.
[6] In equation (I), R ² is the following A2b);

R ^2a is a C ₁ to C ₆ alkyl group or a C ₃ to C ₁₀ cycloalkyl group;
R ^2d and R ^2e are independently C ₁ to C ₆ alkyl groups;
R ^2d and R ^2e may be coupled to each other to form a ring.
The compound according to [5], or a pharmacologically acceptable salt thereof.
[7] In equation (I),
R ³ is *-(CH ₂ ) _x- T- (CR ¹³ R ¹⁴ ) _y- U, and * indicates the binding position with -CH- in formula (I);
T is a bond or -S (O) _p- ;
U is hydrogen atom, C 3 _~ C ₁₀ cycloalkyl group or an aromatic hydrocarbon Hajime Tamaki (the aromatic hydrocarbon ring group may be one or more substituted with halogen atom);
R ¹³ and R ¹⁴ are independent hydrogen atoms or C ₁ to C ₆ alkyl groups, respectively;
x and y are independently integers from 0 to 2;
p is 0;
(However, ^{this does not apply when R 3} is a hydrogen atom or a methyl group)
R ⁵ is the following B1) or C ₁ to C ₆ alkyl group, where * indicates the bonding position with -N- in formula (I);

^{RingB may be substituted with R 17} , R ¹⁸ and R ¹⁹ , respectively, aromatic hydrocarbon ring groups, C ₃ to C ₁₀ cycloalkyl groups, 5 to 10 member heteroaryl groups or 3 to 10 member heterocycloalkyl groups. Is the basis;
R ¹⁷ and R ¹⁸ are independent hydrogen atoms, halogen atoms, hydroxyl groups, amino groups, cyano groups, C ₁ to C ₆ alkyl groups, halo C ₁ to C ₆ alkyl groups, hydroxy C ₁ to C ₆ alkyl groups, respectively. C ₁ to C ₆ alkoxy groups, C ₁ to C ₆ alkylamino groups, C ₁ to C ₆ alkylsulfanyl groups, C ₁ to C ₆ alkoxycarbonyl groups, C ₁ to C ₆ alkylaminocarbonyl groups or C ₁ to C ₆ Acylamino group,
The compound according to [6], or a pharmacologically acceptable salt thereof.
[8] In equation (I),
R ³ is a group represented by *-(CH ₂ ) _x- T- (CR ¹³ R ¹⁴ ) _y- U, and * indicates the binding position with -CH- in formula (I);
T is a bond;
U is a hydrogen atom or a C ₃ to C ₁₀ cycloalkyl group;
R ¹³ and R ¹⁴ are hydrogen atoms;
x and y are each independently an integer of 1-2;
R ⁵ is the following B1) or C ₁ to C ₆ alkyl group, where * indicates the bonding position with -N- in formula (I);

^{RingB may be substituted with R 17} , R ¹⁸ and R ¹⁹ , respectively, aromatic hydrocarbon ring groups, C ₃ to C ₁₀ cycloalkyl groups, 5 to 10 member heteroaryl groups or 3 to 10 member heterocycloalkyl groups. Is the basis;
R ¹⁷ and R ¹⁸ are independently hydrogen atoms, halogen atoms, hydroxyl groups, amino groups, cyano groups, C ₁ to C ₆ alkyl groups, halo C ₁ to C ₆ alkyl groups, hydroxy C ₁ to C ₆ alkyl groups or C ₁ to C ₆ alkoxy groups,
The compound according to [7], or a pharmacologically acceptable salt thereof.
[9] In equation (I),
R ^2a, ^{R 2d} and ^{R 2e} are each independently _C 1 ~ _{C 3} alkyl group;
R ³ is an n-butyl group or a 2-cyclopropylethane-1-yl group,
The compound according to [8], or a pharmacologically acceptable salt thereof.
During [10] Formula (I), ^{R 2} is located at the following A1);

R ^2a , R ^2b and R ^2c are independently C ₁ to C ₆ alkyl groups, C ₁ to C ₆ alkoxycarbonyl groups or C ₃ to C ₁₀ cycloalkyl groups;
R ³ is *-(CH ₂ ) _x- T- (CR ¹³ R ¹⁴ ) _y- U, and * indicates the binding position with -CH- in formula (I);
T is a bond;
U is a hydrogen atom or a C ₃ to C ₁₀ cycloalkyl group;
R ¹³ and R ¹⁴ are hydrogen atoms;
x and y are independently integers of 1 and 2, respectively.
The compound according to [3], or a pharmacologically acceptable salt thereof.
[11] In the formula (I), ^{R 2} is located in the following A1a);

R ^2a is a hydrogen atom or a C ₁ to C ₆ alkyl group;
R ^2f is a C ₁ to C ₆ alkoxy group;
R ^2g is a hydrogen atom or a C ₁ to C ₆ alkoxy group;
R ³ is *-(CH ₂ ) _x- T- (CR ¹³ R ¹⁴ ) _y- U, and * indicates the binding position with -CH- in formula (I);
T is a bond;
U is a hydrogen atom or a C ₃ to C ₁₀ cycloalkyl group;
R ¹³ and R ¹⁴ are hydrogen atoms;
x and y are independently integers of 1 and 2, respectively.
The compound according to [3], or a pharmacologically acceptable salt thereof.
During [12] formula (I), ^{R 5} is less B1a), * indicates the bonding position with -N- in the formula (I);

G is CH or N;
J is bond, -O- or ^{-NR 25} - and is;
R ²⁵ is a hydrogen atom or a C ₁ to C ₆ alkyl group;
K is a hydrogen atom, a cyano group, a C ₁ to C ₆ alkyl group, a halo C ₁ to C ₆ alkyl group or a 3 to 10 member heterocycloalkyl group (the 3 to 10 member heterocycloalkyl group is C ₁ to C _6). It may be substituted with one or more alkyl groups).
The compound according to [2], or a pharmacologically acceptable salt thereof.
[13] In equation (I),
R ³ is *-(CH ₂ ) _x- T- (CR ¹³ R ¹⁴ ) _y- U, and * indicates the binding position with -CH- in formula (I);
T is a bond;
U is a hydrogen atom or a C ₃ to C ₁₀ cycloalkyl group;
R ¹³ and R ¹⁴ are hydrogen atoms;
x and y are independently integers of 1 and 2, respectively.
R ⁵ is B1b) below, and * indicates the binding position with -N- in formula (I);

J is bond, -O- or ^{-NR 25} - and is;
R ²⁵ is a hydrogen atom or a C ₁ to C ₆ alkyl group;
K is a hydrogen atom, a cyano group, a C ₁ to C ₆ alkyl group, a halo C ₁ to C ₆ alkyl group or a 3 to 10 member heterocycloalkyl group (the 3 to 10 member heterocycloalkyl group is C ₁ to C _6). It may be substituted with one or more alkyl groups).
The compound according to [12], or a pharmacologically acceptable salt thereof.
During [14] formula (I), ^{R 5} is less B1c), * indicates the bonding position with -N- in the formula (I);

J is bond, -O- or ^{-NR 25} - and is;
R ²⁵ is a hydrogen atom or a C ₁ to C ₆ alkyl group;
K is a hydrogen atom, a cyano group, a C ₁ to C ₆ alkyl group, a halo C ₁ to C ₆ alkyl group or a 3 to 10 member heterocycloalkyl group (the 3 to 10 member heterocycloalkyl group is C ₁ to C _6). It may be substituted with one or more alkyl groups).
The compound according to [12], or a pharmacologically acceptable salt thereof.
[15] In equation (I), R ² is the following A3).

The compound according to [14], or a pharmacologically acceptable salt thereof.
[16] In equation (I), R ² is the following A3);

n is 0;
R ³ is *-(CH ₂ ) _x- T- (CR ¹³ R ¹⁴ ) _y- U, and * indicates the binding position with -CH- in formula (I);
T is a bond;
U is a hydrogen atom or a C ₃ to C ₁₀ cycloalkyl group;
R ¹³ and R ¹⁴ are hydrogen atoms;
x and y are independently integers of 1 and 2, respectively.
The compound according to [15], or a pharmacologically acceptable salt thereof.
[17] In equation (I), R ² is the following A3);

n is 0;
RingA is optionally substituted aromatic hydrocarbon ring group by ^{R 8} and ^{R 9,}
The compound according to [16], or a pharmacologically acceptable salt thereof.
[18] In equation (I);
R ² is the following A3a);

R ²⁶ is a hydrogen atom or a C ₁ to C ₆ alkyl group;
R ²⁷ and R ²⁸ are independently hydrogen atoms, C ₁ to C ₆ alkyl groups or halo C ₁ to C ₆ alkyl groups, respectively.
The compound according to [17], or a pharmacologically acceptable salt thereof.
[19] In the formula (I), ^{R 5} is a following B1c), * indicates the bonding position with -N- in the formula (I);

J is a bond or -O-;
K is a hydrogen atom or a C ₁ to C ₆ alkyl group,
The compound according to [18], or a pharmacologically acceptable salt thereof.
[20] In equation (I), R ² is the following A3);

n is 1;
R ³ is *-(CH ₂ ) _x- T- (CR ¹³ R ¹⁴ ) _y- U, and * indicates the binding position with -CH- in formula (I);
T is a bond;
U is a hydrogen atom or a C ₃ to C ₁₀ cycloalkyl group;
R ¹³ and R ¹⁴ are hydrogen atoms;
x and y are independently integers of 1 and 2, respectively.
The compound according to [15], or a pharmacologically acceptable salt thereof.
[21] In equation (I), R ² is the following A3);

n is 1;
RingA is an optionally substituted aromatic hydrocarbon ring group by ^{R 8} and ^{R 9;}
R ⁹ is -YZ;
Y is the bond, -O-, -NR ^10- or-(CR ¹¹ R ¹² ) _s- ;
R ¹⁰ , R ¹¹ and R ¹² are independent hydrogen atoms or C ₁ to C ₆ alkyl groups, respectively;
s is an integer from 0 to 6;
Z is a hydrogen atom, a C ₁ to C ₆ alkyl group, a halo C ₁ to C ₆ alkyl group, a C ₁ to C ₆ alkoxy group or a C ₁ to C ₆ alkyl amino group.
The compound according to [20], or a pharmacologically acceptable salt thereof.
[22] The compound represented by the general formula (I) is the following formula (II).

The compound according to [1], or a pharmacologically acceptable salt thereof.
[23] The compound represented by the general formula (I) is the following formula (II);

In formula (II), R ² is the following A2b);

R ^2a is a C ₁ to C ₆ alkyl group, a C ₃ to C ₁₀ cycloalkyl group or a hydroxy C ₁ to C ₆ alkyl group;
R ^2d and R ^2e are independently C ₁ to C ₆ alkyl groups or hydroxy C ₁ to C ₆ alkyl groups;
R ^2d and R ^2e may combine with each other to form a ring;
R ³ is *-(CH ₂ ) _x- T- (CR ¹³ R ¹⁴ ) _y- U, and * indicates the binding position with -CH- in formula (II);
T is a bond;
U is a hydrogen atom or a C ₃ to C ₁₀ cycloalkyl group;
R ¹³ and R ¹⁴ are hydrogen atoms;
x and y are independently integers of 1 and 2, respectively.
The compound according to [22], or a pharmacologically acceptable salt thereof.
[24] The compound represented by the general formula (I) is the following formula (III);

In formula (III), R ² is the following A2b);

R ^2a , R ^2d , and R ^2e are independently C ₁ to C ₃ alkyl groups;
R ³ is *-(CH ₂ ) _x- T- (CR ¹³ R ¹⁴ ) _y- U, and * indicates the binding position with -CH- in formula (III);
T is a bond;
U is a hydrogen atom or a C ₃ to C ₁₀ cycloalkyl group;
R ¹³ and R ¹⁴ are hydrogen atoms;
x and y are independently integers of 1 and 2, respectively.
R ⁵ is below B1), * indicates the bonding position with -N- in the formula (I);

R ¹⁵ and R ¹⁶ are independent hydrogen atoms or C ₁ to C ₆ alkyl groups, respectively;
m is 0 or 1;
RingB is an aromatic hydrocarbon ring group or a 5- to 10-membered heteroaryl group, which may be substituted with ^{R 17} , R ¹⁸ and R ^{19, respectively;}
R ¹⁷ and R ¹⁸ are independently hydrogen atoms, cyano groups, C ₁ to C ₆ alkyl groups or C ₁ to C ₆ alkoxy groups;
R ¹⁹ is-(CR ²⁰ R ²¹ ) _r- V- (CR ²² R ²³ ) _q- Q;
V is a bond, -O- or -NR ^24- ;
R ²⁰ , R ²¹ , R ²² , R ²³ and R ²⁴ are hydrogen atoms;
q and r are independently integers from 0 to 2;
Q is a hydrogen atom, C ₁ to C ₆ alkylamino group or 3 to 10-membered heterocycloalkyl group (the 3 to 10-membered heterocycloalkyl group is substituted with one or more _{C 1} to C _{6 alkyl groups.} May be good);
R ⁴ and R ⁵ may be combined with each other to form a ring.
The compound according to [1], or a pharmacologically acceptable salt thereof.
[25] or less

A compound selected from, or a pharmacologically acceptable salt thereof.
[26] A G9a enzyme-inhibiting composition containing the compound according to any one of [1] to [25] or a pharmacologically acceptable salt thereof as an active ingredient.
[27] A pharmaceutical composition containing the compound according to any one of [1] to [25] or a pharmacologically acceptable salt thereof as an active ingredient.
[28] Proliferative diseases such as cancer, β-globin dysfunction, fibrosis, to which the compound according to any one of [1] to [25] or a pharmaceutically acceptable salt thereof is administered. A method of preventing or treating at least one disease selected from the group of diseases consisting of pain, neurodegenerative diseases, Prader-Willi syndrome, malaria, viral infections, myopathy, and autism.
[29] At least selected from a group of diseases consisting of proliferative diseases such as cancer, β-globin disorders, fibrosis, pain, neurodegenerative diseases, Prader-Willi syndrome, malaria, viral infections, myopathy, and autism. Use of the compound according to any one of [1] to [25] or a pharmaceutically acceptable salt thereof for producing a drug for the prevention or treatment of a kind of disease.
[30] At least selected from a group of diseases consisting of proliferative diseases such as cancer, β-globin disorders, fibrosis, pain, neurodegenerative diseases, Prader Willy syndrome, malaria, viral infections, myopathy, and autism. A pharmaceutical composition containing the compound according to any one of [1] to [25] or a pharmacologically acceptable salt thereof and a pharmaceutically acceptable carrier, which is used for the prevention or treatment of a kind of disease. Stuff.

Compound (I), or a pharmacologically acceptable salt thereof, exhibited, for example, strong G9a enzyme inhibitory activity.
Therefore, the compound (I) according to the present invention or a pharmacologically acceptable salt thereof is a proliferative disease such as cancer, β-globin dysfunction, fibrosis, pain, neurodegenerative disease, Prader-Willi syndrome, etc. It is useful as a therapeutic agent for malaria, viral infections, myopathy, autism, etc. or a preventive agent thereof.
Furthermore, the compound (I) according to the present invention or a pharmacologically acceptable salt thereof has various pathological conditions (for example, β-globin dysfunction such as sickle cell disease, gastric cancer, hepatocellular carcinoma, acute myeloid leukemia). Leukemia such as sex leukemia and chronic myelogenous leukemia, cervical cancer, neuroblastoma, glioma, pancreatic cancer, colon cancer, head and neck squamous cell carcinoma, breast cancer, lung cancer, ovarian cancer, melanoma, lung Fibrosis such as fibrosis and renal fibrosis, pain, neurodegenerative diseases such as Alzheimer's disease, viral infections such as Prader Willy syndrome, malaria, sickle cell disease, vesicular stomatitis, myeloid disease, myopathy, autism, etc.) It is highly useful for treatment, prevention or suppression. In addition, compound (I) according to the present invention or a pharmacologically acceptable salt thereof has high utility in suppressing cancer metastasis and transsexuality.

The terms in this specification will be explained.

The "halogen atom" shown in the present specification means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

As used herein, the "C ₁ to C ₆ alkyl group" means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. C ₁ to C ₆ alkyl groups include, for example, methyl group, ethyl group, 1-propyl group, isopropyl group, 1-butyl group, isobutyl group, sec-butyl group, tert-butyl group, 1-pentyl group, isopentyl group. , Neopentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, 1-hexyl group, isohexyl group and the like. Further, "C _{1 ~} C ₃ alkyl group" means a saturated hydrocarbon radical of straight or branched chain of 1 to 3 carbon.

As used herein, the "C ₂ to C ₆ alkenyl group" means a straight or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and having at least one double bond. As C ₂ ~ _{C 6} alkenyl group include a vinyl group, 2-propenyl group, 1-propenyl group, 1-buten-1-yl group, 1-buten-2-yl group, 1-buten-3-yl group , 2-Buten-1-yl group, 2-butene-2-yl group, 1-penten-1-yl group, 1-penten-2-yl group, 1-penten-3-yl group, 2-penten- 1-yl group, 2-penten-2-yl group, 2-penten-3-yl group, 1-hexene-1-yl group, 1-hexene-2-yl group, 1-hexene-3-yl group, Examples thereof include 2-methyl-1-propen-1-yl group.

As used herein, the "C ₁ to C ₆ acyl group" means an acyl group derived from a linear or branched aliphatic carboxylic acid having 1 to 6 carbon atoms. For example, a formyl group, an acetyl group, a propanoyl group, a 1-butanoyl group, a 1-pentanoyl group, a 1-hexanoyl group and the like can be mentioned.

"Halo C _{1 ~} C ₆ alkyl group" represented herein, means at least one C _{1 ~} C ₆ alkyl group wherein a hydrogen atom is substituted with a halogen atom the same or different. As halo C ₁ to C ₆ alkyl groups, for example, fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 2-chloroethyl group, 2,2-difluoroethyl group, 1,1-difluoroethyl group. Group, 1,2-difluoroethyl group, 1-chloro-2-fluoroethyl group, 2,2,2-trifluoroethyl group, 1,1,2,2,2-pentafluoroethyl group, 2,2 2-Trichloroethyl group, 3-fluoropropyl group, 2-fluoropropyl group, 1-fluoropropyl group, 3,3-difluoropropyl group, 2,2-difluoropropyl group, 1,1-difluoropropyl group, 4- Fluorobutyl group, 5-fluoropentyl group, 6-fluorohexyl group and the like can be mentioned.

_{The "hydroxy C 1} to C ₆ alkyl group" shown in the present specification _{means the above C 1} to C ₆ alkyl group in which at least one hydrogen atom is substituted with a hydroxyl group. As hydroxy C ₁ to C ₆ alkyl groups, for example, hydroxymethyl group, 1-hydroxyethyl group, 1-hydroxy-1,1-dimethylmethyl group, 2-hydroxyethyl group, 2-hydroxy-2-methylpropyl group, Examples thereof include a 3-hydroxypropyl group. Further, the "hydroxy C ₁ to C ₃ alkyl group" means a hydroxy alkyl group having 1 to 3 carbon atoms.

As used herein, the term "C ₁ to C ₆ alkoxy group" means a linear or branched alkoxy group having 1 to 6 carbon atoms. C ₁ to C ₆ alkoxy groups include, for example, methoxy group, ethoxy group, 1-propoxy group, isopropoxy group, isobutoxy group, 1-butoxy group, sec-butoxy group, tert-butoxy group, 1-pentyloxy group, 1-Hexyloxy group and the like can be mentioned.

"Halo C _{1 ~} C ₆ alkoxy group" represented herein, means at least one C _{1 ~} C ₆ alkoxy group in which a hydrogen atom is substituted with a halogen atom the same or different. As halo C ₁ to C ₆ alkoxy groups, for example, monofluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, 2-chloroethoxy group, 2-fluoroethoxy group, 2,2-difluoroethoxy group, 1,1- Difluoroethoxy group, 1,2-difluoroethoxy group, 1-chloro-2-fluoroethoxy group, 2,2,2-trifluoroethoxy group, 1,1,2,2,2-pentafluoroethoxy group, 2, 2,2-Trichloroethoxy group, 3-fluoropropoxy group, 2-fluoropropoxy group, 1-fluoropropoxy group, 3,3-difluoropropoxy group, 2,2-difluoropropoxy group, 1,1-difluoropropoxy group, Examples thereof include 4-fluorobutoxy group, 5-fluoropentyloxy group, 6-fluorohexyloxy group and the like.

As used herein, the "C ₁ to C ₆ alkoxycarbonyl group" means a carbonyl group to which a linear or branched alkoxy group having 1 to 6 carbon atoms is bonded. C ₁ to C ₆ alkoxycarbonyl groups include, for example, methoxycarbonyl group, ethoxycarbonyl group, 1-propoxycarbonyl group, isopropoxycarbonyl group, isobutoxycarbonyl group, 1-butoxycarbonyl group, sec-butoxycarbonyl group, tert- Examples thereof include a butoxycarbonyl group, a 1-pentyloxycarbonyl group and a 1-hexyloxycarbonyl group.

The "C ₁ to C ₆ alkylamino groups" referred to herein are linear or branched alkyl groups in which one or two hydrogen atoms of the amino group have a total carbon number of 1 to 6. Means a substituted amino group. C ₁ to C ₆ alkylamino groups include, for example, methylamino group, ethylamino group, 1-propylamino group, isopropylamino group, 1-butylamino group, isobutylamino group, sec-butylamino group, tert-butylamino group. Group, 1-pentylamino group, isopentylamino group, neopentylamino group, 1-methylbutylamino group, 2-methylbutylamino group, 1,2-dimethylpropylamino group, 1-hexylamino group, isohexylamino Examples thereof include a group, a dimethylamino group, a diethylamino group, an N-ethyl-N-methylamino group, and an N-ethyl-N-propylamino group.

As used herein, the "C ₁ to C ₆ alkylaminocarbonyl group" means a carbonyl group to which a linear or branched alkylamino group having 1 to 6 total carbon atoms is bonded. C ₁ to C ₆ alkylaminocarbonyl groups include, for example, methylaminocarbonyl group, ethylaminocarbonyl group, 1-propylaminocarbonyl group, isopropylaminocarbonyl group, 1-butylaminocarbonyl group, isobutylaminocarbonyl group, sec-butyl. Aminocarbonyl group, tert-butylaminocarbonyl group, 1-pentylaminocarbonyl group, isopentylaminocarbonyl group, neopentylaminocarbonyl group, 1-methylbutylaminocarbonyl group, 2-methylbutylaminocarbonyl group, 1,2- Dimethylpropylaminocarbonyl group, 1-hexylaminocarbonyl group, isohexylaminocarbonyl group, dimethylaminocarbonyl group, diethylaminocarbonyl group, N-ethyl-N-methylaminocarbonyl group, N-ethyl-N-propylaminocarbonyl group, etc. Can be mentioned.

As used herein, the term "C ₁ to C ₆ acylamino group" means that one or two hydrogen atoms of an amino group are replaced with a linear or branched acyl group having 1 to 6 carbon atoms. It means an amino group. Examples of the C ₁ to C ₆ acylamino group include a formylamino group, an acetylamino group, a 1-propanoylamino group, a 1-butanoylamino group, a 1-pentanoylamino group, a hexanoylamino group and the like.

_{The "C 1} to C ₆ alkylsulfanil group" shown in the present specification means a group in which a linear or branched alkyl group having 1 to 6 carbon atoms is bonded to a sulfur atom. C ₁ to C ₆ alkylsulfanyl groups include, for example, methylsulfanyl group, ethylsulfanyl group, 1-propylsulfanyl group, isopropylsulfanyl group, 1-butylsulfanyl group, isobutylsulfanyl group, sec-butylsulfanyl group, tert-butylsulfanyl group. The group etc. can be mentioned.

"Halo C _{1 ~} C ₆ alkylsulfanyl group" represented herein, means at least one C ₁ hydrogen atom is substituted with a halogen atom the same or different _~ C ₆ alkylsulfanyl group. As halo C ₁ to C ₆ alkylsulfanyl groups, for example, fluoromethylsulfanyl group, difluoromethylsulfanyl group, trifluoromethylsulfanyl group, 2-fluoroethylsulfanyl group, 2-chloroethylsulfanyl group, 2,2-difluoroethylsulfanyl Group, 1,1-difluoroethyl sulfanyl group, 1,2-difluoroethyl sulfanyl group, 1-chloro-2-fluoroethyl sulfanyl group, 2,2,2-trifluoroethyl sulfanyl group, 1,1,2,2 , 2-Pentafluoroethyl sulfanyl group, 2,2,2-trichloroethyl sulfanyl group, 3-fluoropropyl sulfanyl group, 2-fluoropropyl sulfanyl group, 1-fluoropropyl sulfanyl group, 3,3-difluoropropyl sulfanyl group, Examples thereof include 2,2-difluoropropylsulfanyl group, 1,1-difluoropropylsulfanyl group, 4-fluorobutylsulfanyl group, 5-fluoropentylsulfanyl group, 6-fluorohexylsulfanyl group and the like.

Examples of the "aromatic hydrocarbon ring group" shown in the present specification include a phenyl group, an indenyl group, a 1-naphthyl group, a 2-naphthyl group, an azulenyl group, a heptalenyl group, a biphenyl group, an indasenyl group, an acenaphthyl group and a fluorenyl group. Examples thereof include a group, a phenylenyl group, a phenylanthrenyl group, an anthracenyl group, a benzocyclooctenyl group and the like.

The "5- to 10-membered heteroaryl group" referred to herein independently comprises 1 to 4 intracyclic heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms. It means a ~ 10-membered monocyclic aromatic heterocyclic group or fused aromatic heterocyclic group, and the nitrogen and sulfur atoms may be optionally oxidized (ie, N → O, SO or SO ₂ ). Examples of 5- to 10-membered heteroaryl groups include, but are not limited to, benzoimidazolyl group, benzofuranyl group, benzothiofuranyl group, benzothiophenyl group, benzoxazolyl group, benzoxazolinyl group, benzothiazolyl group, benzo. Triazolyl group, benzoisoxazolyl group, benzoisothiazolyl group, benzoimidazolinyl group, furanyl group, imidazolidinyl group, imidazolyl group, 1H-indazolyl group, imidazolopyridinyl group, indolenyl group, indridinyl group, 3H-Indrill Group, Isobenzofuranyl Group, Isoindazolyl Group, Isoindrill Group, Isoquinolinyl Group, Isothiazolyl Group, Isothiazolopyridinyl Group, Isoxazolyl Group, Isoxazolopyridinyl Group, Naftyridinyl Group, 1,2,3- Oxaziazolyl group, 1,2,4-oxadiazolyl group, 1,2,5-oxadiazolyl group, 1,3,4-oxadiazolyl group, oxazolidinyl group, oxazolyl group, oxazolopyridinyl group, oxazolidinyl perimidinyl Group, oxyindrill group, pyrimidinyl group, pyrazinyl group, pyrazolydinyl group, pyrazolinyl group, pyrazolopyridinyl group, pyrazolyl group, pyridadinyl group, pyridooxazolyl group, pyridoimidazolyl group, pyridothiazolyl group, pyridinyl group, Pyrrolopyridinyl group, quinazolinyl group, quinolinyl group, 4H-quinolinidinyl group, quinoxalinyl group, quinucridinyl group, tetrazolyl group, 6H-1,2,5-thiadiazinyl group, 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl Group, 1,2,5-thiazolyl group, 1,3,4-thiadiazolyl group, thianthrenyl group, thiazolyl group, thienyl group, thiazolopyridinyl group, thienothiazolyl group, thienooxazolyl group, thienoimidazolyl group, thiophenyl Examples thereof include a group, a triazinyl group, a 1,2,3-triazolyl group, a 1,2,4-triazolyl group, a 1,2,5-triazolyl group and a 1,3,4-triazolyl group. Also included are fused ring and spiro ring compounds containing the above heterocycles.

_{The "C 3} to C ₁₀ cycloalkyl group" shown in the present specification means a monocyclic or bicyclic saturated alicyclic hydrocarbon group having 3 to 10 carbon atoms, and is a crosslinked type or a spiro type. Can be. Examples of the C ₃ to C ₁₀ cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a spiroheptyl group, a spirooctyl group, an octahydropentalenyl group and the like. Can be mentioned. Further, the C ₃ to C ₁₀ cycloalkyl group may be condensed with an additional aromatic hydrocarbon ring group or 5 to 10-membered heteroaryl group, and the aromatic hydrocarbon ring group or 5 to 10-membered heteroaryl group may be condensed. Examples of the condensed C ₃ to C ₁₀ cycloalkyl groups include a dihydroindenyl group and a tetrahydronaphthyl group.
Further, the “C ₃ to C ₄ cycloalkyl group” means a cycloalkyl group having 3 to 4 carbon atoms.

The "3 to 10-membered heterocycloalkyl group" shown herein independently comprises 1 to 4 intracyclic heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms. , Monocyclic, bicyclic, or tricyclic 3- to 10-membered ring heterocycloalkyl groups, where nitrogen and sulfur heteroatoms may be optionally oxidized (ie, N → O, SO). Or SO ₂ ), the nitrogen atom may or may not be substituted, may have 1 to 3 carbonyl groups, and may have one double bond in the ring. May be good. Further, the 3- to 10-membered heterocycloalkyl group can be a crosslinked type or a spiro type. The 3- to 10-membered heterocycloalkyl groups may be condensed with additional aromatic hydrocarbon ring groups or 5- to 10-membered heteroaryl groups. Examples of the 3- to 10-membered heterocycloalkyl group include an aziridinyl group, an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, an azepanyl group, an azocanyl group, a dihydropyrrolill group, a tetrahydropyridinyl group, a piperazinyl group, a morpholinyl group and a thiomorpholinyl group. 1-Oxidethiomorpholinyl group, 1,1-dioxidethiomorpholinyl group, oxazepinyl group, thiazepanyl group, 1-oxide-1,4-thiazepanyl group, 1,1-dioxide-1,4-thiazepanyl group , 1,4-Diazepanyl group, 1,4-oxazocanyl group, 1,5-oxazocanyl group, oxetanyl group, tetrahydrofuranyl group, tetrahydropyranyl group, octahydrocyclopenta [c] pyrrolyl group, 3-azabicyclo [3. 2.0] heptanyl group, 3-azabicyclo [3.1.0] hexanyl group, 5-azabicyclo [2.1.1] hexanyl group, 2-azabicyclo [2.1.1] hexanyl group, 2-azabicyclo [ 4.1.0] heptanyl group, 3-azabicyclo [4.1.0] heptanyl group, 2-azabicyclo [4.2.0] octanyl group, 3-azabicyclo [4.2.0] octanyl group, 3- Azabicyclo [3.1.1] heptanyl group, 2-azabicyclo [2,2,1] heptanyl group, 6-azabicyclo [3.1.1] heptanyl group, 8-azabicyclo [3.2.1] octanyl group, 3-azabicyclo [3.2.1] octanyl group, 6-azabicyclo [3.2.1] octanyl group, 4-azaspiro [2.4] heptanyl group, 5-azaspiro [2.4] heptanyl group, 1- Oxo-5-azaspiro [2.4] heptanyl group, 5-azaspiro [3.4] octanyl group, 6-azaspiro [3.4] octanyl group, 2-oxo-6-azaspiro [3.4] octanyl group, 1-oxo-6-azaspiro [3.4] octanyl group, 4-azaspiro [2.5] octanyl group, 5-azaspiro [2.5] octanyl group, 6-azaspiro [2.5] octanyl group, 1- Oxa-5-azaspiro [2.5] octanyl group, 4-oxa-7-azaspiro [2.5] octanyl group, 1-oxa-6-azaspiro [2.5] octanyl group, 2,6-diazaspiro [3] .4] Octanyl group and the like.

The term "bonding to each other to form a ring" as used herein means to remove one hydrogen atom from each of the two substituents forming the ring and to bond the hydrogen-excluded sites to each other. Means. For example, when the methylene group has two substituents and the two substituents forming the ring are a methyl group and a 1-hydroxyethyl group,

Can be mentioned.

"3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxylic acid" or "3,6,6-trimethyl-4-oxo-4" as shown herein. , 5, 6, 7-Tetrahydro-1H-Indole-2-carboxylic Acid ”both represent the same or less compound A, and the related compounds follow the same nomenclature.

Hereinafter, this embodiment will be described in more detail.

In the following, regarding the definition of the functional group of the general formula, the description may be omitted by quoting the definition already described. The cited definition refers to the definition described in the description of the embodiments described below.

Regarding the definition of the functional group of the general formula, unless otherwise specified, the definition represented by the same code is common to each general formula including the code.

The present embodiment relates to a compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof.
General formula (I):

R ¹⁵ and R ¹⁶ are independently hydrogen atoms, C ₁ to C ₆ alkyl groups or hydroxy C ₁ to C ₆ alkyl groups;
R ¹⁵ and R ¹⁶ may combine with each other to form a ring;
R ¹⁵ and R ¹⁶ may combine with Ring B to form a ring;
m is 0 or 1;
^{RingB may be substituted with R 17} , R ¹⁸ and R ¹⁹ , respectively, aromatic hydrocarbon ring groups, C ₃ to C ₁₀ cycloalkyl groups, 5 to 10 member heteroaryl groups or 3 to 10 member heterocycloalkyl groups. Is the basis;
R ¹⁷ and R ¹⁸ are independently hydrogen atom, halogen atom, hydroxyl group, amino group, cyano group, carbamoyl group (-CONH ₂ ), C ₁ to C ₆ alkyl group, halo C ₁ to C ₆ alkyl group, hydroxy. C ₁ to C ₆ alkyl groups, C ₁ to C ₆ alkoxy groups, C ₁ to C ₆ alkyl amino groups, C ₁ to C ₆ alkyl sulfanyl groups, halo C ₁ to C ₆ alkyl sulfanyl groups, C ₁ to C ₆ acyls Group, C ₁ to C ₆ alkoxycarbonyl group, C ₁ to C ₆ alkylaminocarbonyl group or C ₁ to C ₆ acylamino group;
R ¹⁹ is-(CR ²⁰ R ²¹ ) _r- V- (CR ²² R ²³ ) _q- Q;
V is a bond, -O-, -NR ^24- or -S (O) _t- ;
t is an integer between 0 and 2;
R ²⁰ , R ²¹ , R ²² , R ²³ and R ²⁴ are independently hydrogen atoms or C ₁ to C ₆ alkyl groups;
q and r are independently integers from 0 to 6;
Q is a hydrogen atom, an amino group, a hydroxyl group, a C ₁ to C ₆ alkyl group, a C ₁ to C ₆ alkyl amino group, a C ₃ to C ₁₀ cycloalkyl group, a 5 to 10 member heteroaryl group or a 3 to 10 member heterocyclo. Alkyl groups (the C ₁ to C ₆ alkylamino groups, C ₃ to C ₁₀ cycloalkyl groups, 5 to 10 member heteroaryl groups and 3 to 10 member heterocycloalkyl groups are halogen atoms, C ₁ to C ₆ alkyl groups. , C ₁ to C ₆ alkoxy groups, C ₁ to C ₆ alkylamino groups, C ₁ to C ₆ alkoxycarbonyl groups, C ₁ to C ₆ alkylaminocarbonyl groups, hydroxy C ₁ to C ₆ alkyl groups. It may be substituted with one or more substituents);
R ¹⁷ , R ¹⁸ and R ¹⁹ may combine with each other to form a ring;
Bonded together R ⁴ and R ⁵ may form a ring;
When R ¹ is a nitrogen atom, m is 0, and Ring B is a phenyl group that may be substituted with ^{R 17} , R ¹⁸ and R ¹⁹ ^{, R 1} and the phenyl group combine to form a benzimidazole ring. May]
A compound represented by, or a pharmacologically acceptable salt thereof.

Preferred compounds of this embodiment include, for example, the following compounds.

Furthermore, compound (I) of the present embodiment, or a pharmacologically acceptable salt thereof, may exist as a hydrate or a solvate. Any hydrate and solvate formed by the derivative represented by the general formula (I) or a salt thereof, including the preferred compounds specifically described above, are all included in the scope of the present invention. To. Examples of the solvent that can form a solvate include methanol, ethanol, isopropyl alcohol, acetone, ethyl acetate, dichloromethane, diisopropyl ether and the like.

The compound (I) of the present embodiment can be a pharmacologically acceptable salt thereof, if necessary. A pharmacologically acceptable salt means a salt with a pharmaceutically acceptable non-toxic base or acid (eg, an inorganic or organic base and an inorganic or organic acid). The pharmaceutically acceptable salt of the compound (I) of the present embodiment is described in the 5th Edition Experimental Chemistry Course (edited by The Chemical Society of Japan, published by Maruzen Co., Ltd.), J. Mol. Pharm. Sci. 1977, 66, 1-19, and "Handbook of Physical Salts: Properties, Selection, and Use" by Sthal and Germany (Wiley-VCH, Weinheim) Can be done.

Salts derived from pharmaceutically acceptable non-toxic bases include salts with inorganic bases such as sodium salt, potassium salt, calcium salt and magnesium salt, and organic bases such as piperidine, morpholine, pyrrolidine, arginine and lysine. Salt can be mentioned.

Examples of salts derived from pharmaceutically acceptable non-toxic acids include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and nitrate, formic acid, acetic acid, maleic acid, fumaric acid and succinic acid. , Lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, paratoluenesulfonic acid, salicylic acid, stearic acid, palmitic acid and other acid addition salts with organic acids.

The compound (I) of the present embodiment, or a pharmacologically acceptable salt thereof, also includes stereoisomers such as a racemate and an optically active substance.

When the compound (I) of the present embodiment is an optical isomer having one or more asymmetric carbon atoms or sulfur atoms, the compound (I) of the present embodiment has a configuration at each asymmetric carbon atom or sulfur atom. However, it may be in either the R arrangement or the S arrangement. The present invention also includes any single enantiomer, a single diastereomer, a mixture of enantiomers or a mixture of diastereomers. Further, in a mixture of optically active substances, a racemate composed of equal amounts of each optical isomer is also included in the scope of the present invention. When compound (I) of the present embodiment is a racemic solid or crystal, racemic compounds, racemic mixtures and racemic solid solutions are also included within the scope of the invention.

In compound (I) of the present embodiment, the diastereomeric mixture can be separated into the respective diastereomers by a conventional method such as chromatography or crystallization. It is also possible to make each diastereomer by using a stereochemically single starting material or by a synthetic method using a stereoselective reaction.

When a geometric isomer such as a cis isomer and a trans isomer is present in the compound (I) of the present embodiment, the present invention includes any of the geometric isomers.

When a tautomer is present in the compound (I) of the present embodiment, the present invention includes any of the tautomers.

Compound (I), or a pharmaceutically acceptable salt of the present embodiment, isotope may be ^{^{(e.g., 3 H, 14 C, 35}} S , etc.) or the like labeled compounds. The compound is also included in the present invention.

Furthermore, Compound (I), or salt thereof pharmacologically acceptable in this embodiment may be a deuterium converter which converts the ^{1 H} ² to ^H (D). The compound is also included in the present invention.

Method for Producing Compound (I) of the Present Embodiment The compound (I) of the present embodiment is, for example, a method described in detail in the following synthetic routes 1 to 46 or a method similar thereto, or a method described in other documents or a method thereof. It can be manufactured according to the same method.
The compounds (2) to (122) in the formula may form a salt, and examples of such a salt include those similar to the salt of the compound (I). Further, the compound obtained in each step can be used as it is in the reaction solution or after being obtained as a crude product in the next reaction, but it can be used by a separation means such as recrystallization, distillation, chromatography or the like from the reaction mixture according to a conventional method. It can be easily isolated and purified.

[Synthetic pathway 1]
Among the compounds (I), when R ¹ is an oxygen atom, that is, when it is represented by the compound (2), for example, the method shown in the synthetic route 1 or a method similar thereto, or other methods described in the literature or It can be produced according to a method similar to them.

(In the formula, R ²⁹ represents a C ₁ to C ₆ alkyl group, X represents a halogen atom such as a chlorine atom or a bromine atom, and R ² , R ³ , R ⁴ and R ⁵ are synonymous with those described above. .)

Process 1-1
Compound (5) can be produced by amidating compound (3) with compound (4a) or compound (4b).
As reaction conditions, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, ethyl acetate, dichloromethane, acetonitrile, toluene, benzene, 1,4-dioxane, tetrahydrofuran, etc., or a mixture thereof. Compound (4a), compound (4b), or the like is added to the solvent, and the mixture can be carried out at 0 ° C. to room temperature, and in some cases, heated reflux. If necessary, a base such as triethylamine or N, N-diisopropylethylamine can be added. If necessary, 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium-3-oxide hexafluorophosphate (HATU), 1-ethyl -3- (3-Dimethylaminopropyl) Carbodiimide (EDCI), N, N'-Dicyclohexylcarbodiimide (DCC), or 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4 Condensing agents such as -methylmorpholinium chloride (DMT-MM), N, N-dimethyl-4-aminopyridine, pyridine, 1-hydroxybenzotriazole (HOBT), 1-hydroxy-7-azabenzotriazole (HOAt) ) And other reaction accelerators can be added.

Process 1-2
Compound (6) can be produced by hydrolyzing compound (5).
As reaction conditions, lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, carbonic acid in water, methanol, ethanol, 1-propanol, isopropyl alcohol, tetrahydrofuran, 1,4-dioxane, etc., or a water-containing mixed solvent thereof. By adding an alkali metal salt such as sodium or cesium carbonate, it can be carried out at 0 ° C. to heated reflux under basic conditions. Further, by adding hydrogen chloride or the like in water, tetrahydrofuran, 1,4-dioxane, or a water-containing mixed solvent thereof, it can be carried out under acidic conditions from 0 ° C. to heated reflux.

Process 1-3
Compound (2) can be produced by amidating compound (6) with compound (7).
As the reaction conditions, compound (7) or a salt thereof, for example, aniline, benzylamine and the like can be added, and the same method as in Step 1-1 can be carried out.

[Synthetic pathway 2]
The above-mentioned compound (2) can also be produced, for example, according to the method shown in Synthetic Route 2, or a method similar thereto, or any other method described in the literature or a method similar thereto.

(In the equation, R ² , R ³ , R ⁴ and R ⁵ are synonymous with those described above.)

Process 2-1
Compound (8) can be produced by esterifying compound (6) with pentafluorophenol.
As a reaction condition, pentafluorophenol is added, and the reaction can be carried out in the same manner as in Step 1-3.

Process 2-2
Compound (2) can be produced by amidating compound (8) with compound (7).
As reaction conditions, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, ethyl acetate, dichloromethane, acetonitrile, toluene, benzene, 1,4-dioxane, tetrahydrofuran, etc., or a mixture thereof. Compound (7) or a salt thereof, for example, aniline, benzylamine, etc., can be added to the solvent, and the mixture can be carried out at −78 ° C. to heated reflux. Further, if necessary, triethylamine, N, N-diisopropylethylamine, pyridine and the like can be added.

[Synthetic pathway 3]
The above-mentioned compound (2) can also be produced, for example, according to the method described in detail in the synthetic route 3 or a method similar thereto, or any other method described in the literature or a method similar thereto.

(In the formula, PG represents a protecting group such as tert-butoxycarbonyl group, benzyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl group, benzyl group, acetyl group, benzoyl group or tert-butyldimethylsilyl group. X, R ² , R ³ , R ⁴ and R ⁵ are synonymous with those described above.)

Process 3-1
Compound (10) can be produced by amidating compound (9) with compound (7).
As the reaction conditions, the same method as in Step 1-3 can be used.

Process 3-2
Compound (11) can be produced by removing the protecting group of compound (10).
As reaction conditions, when PG is a tert-butoxycarbonyl group, trifluoro in dichloromethane, chloroform, 1,4-dioxane, tetrahydrofuran, toluene, benzene, methanol, ethanol, ethyl acetate, water, etc., or a mixed solvent thereof. Add an acid such as acetic acid, paratoluene sulfonic acid, hydrogen chloride, hydrobromic acid, sulfuric acid, boron trifluoride diethyl ether complex, boron trifluoride, or aluminum chloride and heat from -78 ° C to room temperature, in some cases. It can be done by reflux.
When PG is a benzyloxycarbonyl group, methanol, ethanol, isopropyl alcohol, 1,4-dioxane, 1,2-dimethoxyethane, ethyl acetate, water, tetrahydrofuran, tert-butylmethyl ether, N, N-dimethylformamide, toluene Etc., or in a mixed solvent thereof, under a hydrogen atmosphere, a catalyst such as palladium carbon, rhodium carbon, platinum carbon, or platinum oxide can be added and carried out at 0 ° C. to heated reflux. If necessary, an acid such as acetic acid, trifluoroacetic acid, or 2,2,2-trifluoroethanol can be added as a reaction accelerator. Alternatively, methanol, ethanol, isopropyl alcohol, 1,4-dioxane, 1,2-dimethoxyethane, ethyl acetate, water, tetrahydrofuran, tert-butylmethyl ether, N, N-dimethylformamide, toluene, etc., or a mixed solvent thereof. It can be carried out by adding an acid such as trifluoroacetic acid and heating at 0 ° C. to reflux.

Process 3-3
Compound (2) can be produced by amidating compound (11) with compound (4a) or compound (4b).
As reaction conditions, compound (4a), compound (4b), or the like can be added, and the same method as in step 1-1 can be used.

[Synthetic pathway 4]
When the above-mentioned compound (2) is represented by the compound (2a) or the compound (2b), for example, the method described in detail in the following synthetic route 4 or a method similar thereto, or other methods described in the literature or the same. It can be manufactured according to the same method.

(In the formula, LG represents a halogen atom such as a chlorine atom or a bromine atom, or a leaving group such as a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group or a paratoluenesulfonyloxy group, and R ³⁰ and R ³¹ are independent of each other. Represents a hydrogen atom, C ₁ to C ₆ alkyl group or halo C ₁ to C ₆ alkyl group, and R ³⁰ and R ³¹ may be bonded to each other to form a ring, PG, R ² , R ³ , R. ⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ²⁰ , R ²¹ , R ²² , R ²³ , Ring B, V, m, r and q are synonymous with those described above.)

Process 4-1
Compound (13) can be produced by converting the hydroxyl group of compound (12) into an appropriate leaving group (LG) such as a halogen atom, a methanesulfonyloxy group, or a paratoluenesulfonyloxy group.
For example, when LG is a chlorine atom, a chlorinating agent such as thionyl chloride or phosphorus oxychloride in dichloromethane, chloroform, benzene, toluene, N, N-dimethylformamide, tetrahydrofuran, pyridine, diethyl ether, etc., or a mixed solvent thereof. Can be added and carried out at −78 ° C. to heating reflux.
Further, for example, when LG is a bromine atom, a brominating agent such as carbon tetrabromide or N-bromosuccinimide in dichloromethane, 1,2-dichloroethane, acetonitrile, tetrahydrofuran, toluene or the like, or a mixed solvent thereof, and tri It can be carried out by adding a phosphorus reagent such as phenylphosphine and heating at −78 ° C. to reflux.
Further, for example, when LG is a methanesulfonyloxy group, a methanesulfonyl agent such as methanesulfonyl chloride is added in dichloromethane, chloroform, 1,4-dioxane, tetrahydrofuran, toluene, benzene, water, etc., or a mixed solvent thereof. However, it can be carried out at −78 ° C. to room temperature, and in some cases, by heating and refluxing. Further, if necessary, a base such as triethylamine, N, N-diisopropylethylamine, or pyridine can be added.
Further, for example, when LG is a paratoluenesulfonyloxy group, paratoluenesulfonyl chloride or the like is formed in dichloromethane, chloroform, 1,4-dioxane, tetrahydrofuran, toluene, benzene, water or the like, or a mixed solvent thereof. It can be carried out by adding an agent and heating at −78 ° C. to room temperature, and in some cases, heating and refluxing. Further, if necessary, a base such as triethylamine, N, N-diisopropylethylamine, or pyridine can be added.

Process 4-2
Compound (2a) can be produced by reacting compound (13) with compound (14).
As reaction conditions, dichloromethane, 1,2-dichloroethane, benzene, toluene, tetrahydrofuran, N, N-dimethylformamide, 1,4-dioxane, acetonitrile and the like, or a mixed solvent thereof, compound (14), or a salt thereof. For example, methylamine, dimethylamine, or a tetrahydrofuran solution containing them can be added, and the mixture can be carried out at −78 ° C. to heated reflux. If necessary, sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, N, N-diisopropylethylamine, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), Alternatively, a base such as 1,5-diazabicyclo [4.3.0] nona-5-ene (DBN) can be added.

Process 4-3
Compound (16) can be produced by reacting compound (13) with compound (15).
As reaction conditions, dichloromethane, 1,2-dichloroethane, benzene, toluene, tetrahydrofuran, N, N-dimethylformamide, 1,4-dioxane, acetonitrile and the like, or a mixed solvent thereof, compound (15), or a salt thereof. For example, di-tert-butyl iminodicarboxylic acid or the like can be added, and the mixture can be carried out at −78 ° C. to heated reflux. If necessary, sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, N, N-diisopropylethylamine, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), Alternatively, a base such as 1,5-diazabicyclo [4.3.0] nona-5-ene (DBN) can be added.

Process 4-4
Compound (2b) can be produced by removing the protecting group of compound (16).
When the PG is a tert-butoxycarbonyl group as the reaction conditions, the same method as in Step 3-2 can be used.

[Synthetic pathway 5]
When the above-mentioned compound (2) is represented by the compound (2c), for example, it is produced according to the method described in detail in the following synthetic route 5 or a method similar thereto, or other methods described in the literature or a method similar thereto. be able to.

(In the formula, R ³² represents a C ₁ to C ₆ alkyl group, R ³³ and R ³⁴ independently represent a hydrogen atom or a C ₁ to C ₆ alkyl group, and R ³³ and R ³⁴ are bonded to each other. Rings may be formed, and R ² , R ³ , R ⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , Ring B and m are synonymous with those described above.)

Process 5-1
Compound (18) can be produced by hydrolyzing compound (17).
As the reaction conditions, it can be carried out in the same manner as in Step 1-2.

Process 5-2
Compound (2c) can be produced by amidating compound (18) with compound (19).
As reaction conditions, compound (19), for example, a solution of ammonia-containing methanol, ethanol, 1,4-dioxane, water, etc., ammonium chloride, ammonium acetate, ammonium formate, or primary amine, secondary amine Or, salts thereof, for example, methylamine, dimethylamine, or a tetrahydrofuran solution containing them, and the like can be added, and the same method as in Steps 1-3 can be carried out.

[Synthetic pathway 6]
When the above-mentioned compound (2) is represented by the compound (2d), for example, it is produced according to the method described in detail in the following synthetic route 6 or a method similar thereto, or other methods described in the literature or a method similar thereto. can do.

(In the formula, R ² , R ³ , R ⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , Ring B and m are synonymous with those described above.)

Process 6-1
Compound (2d) can be produced by reducing the nitro group of compound (20).
As the reaction conditions, general nitro group reduction conditions can be used. For example, methanol, ethanol, isopropyl alcohol, 1,4-dioxane, 1,2-dimethoxyethane, ethyl acetate, water, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, N, N-dimethylformamide, toluene, n-hexane. Etc., or in a mixed solvent thereof, iron powder, zinc powder, tin (II) chloride, metallic tin, metallic indium, metallic sumarium, lane nickel, formic acid, sodium borohydride, nickel borohydride, cobalt hydride, hydrogen. It can be carried out by using lithium aluminum carbonate, sodium dithionate, sodium sulfide, sodium borohydride, hydrazine and the like at 0 ° C. to room temperature, and in some cases, heating and refluxing. Acids such as ammonium chloride, hydrogen chloride, acetic acid, trifluoroacetic acid, sulfuric acid, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, tripotassium phosphate, sodium hydrogencarbonate, carbonic acid, if necessary. Bases such as potassium hydrogen hydrogen, pyridine, triethylamine, or N, N-diisopropylethylamine can be added. Alternatively, methanol, ethanol, isopropyl alcohol, 1,4-dioxane, 1,2-dimethoxyethane, acetic acid, ethyl acetate, water, tetrahydrofuran, tert-butylmethyl ether, N, N-dimethylformamide, toluene and the like, or theirs. It is also possible to reduce by adding a catalyst such as palladium carbon, rhodium carbon, platinum carbon, or platinum oxide in a mixed solvent under a hydrogen atmosphere.

[Synthetic pathway 7]
When the above-mentioned compound (2) is represented by the compound (2e) or the compound (2f), for example, the method described in detail in the following synthetic route 7 or a method similar thereto, or other methods described in the literature or the same. It can be manufactured according to the same method.

(In the formula, A represents a carbon atom or a nitrogen atom, R ³⁵ , R ³⁶ and R ³⁷ each independently represent a hydrogen atom or a C ₁ to C ₆ alkyl group, and a and b independently represent 0 to 0 to each. Represents an integer of 3, PG, R ² , R ³ , R ⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ²⁰ , R ²¹ , R ²² , R ²³ , Ring B, V, m, r and q Is synonymous with the above.)

Process 7-1
Compound (2e) can be produced by reducing alkylation using compound (21) and compound (22).
The reaction conditions include dichloromethane, 1,2-dichloroethane, chloroform, 1,4-dioxane, tetrahydrofuran, toluene, benzene, methanol, ethanol, etc., or a mixed solvent thereof, such as compound (22), paraformaldehyde, an aqueous formalin solution, or the like. Add glycolaldehyde dimer, etc., and add reducing agents such as sodium borohydride, sodium borohydride, sodium borohydride, lithium borohydride, borane-dimethylsulfide complex, lithium aluminum hydride, 2-picorylborane, etc. However, it can be carried out at −78 ° C. to room temperature, and in some cases, by heating and refluxing. Alternatively, methanol, ethanol, isopropyl alcohol, 1,4-dioxane, 1,2-dimethoxyethane, ethyl acetate, water, tetrahydrofuran, tert-butylmethyl ether, N, N-dimethylformamide, toluene, etc., or a mixed solvent thereof. It is also possible to add a catalyst such as palladium carbon, rhodium carbon, platinum carbon, or platinum oxide under a medium or hydrogen atmosphere for reduction. If necessary, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, boron trifluoride diethyl ether complex, boron tribromide, aluminum chloride, chlorotrimethylsilane, 2,2,2-trifluoroethanol, tetra orthotitanium acid A reaction accelerator such as isopropyl can be added.

Process 7-2
Compound (24) can be produced by reducing alkylation with compound (21) and compound (23).
As the reaction conditions, it can be carried out in the same manner as in Step 7-1.

Process 7-3
Compound (2f) can be produced by removing the protecting group of compound (24).
As reaction conditions, when PG is a benzyl group, methanol, ethanol, isopropyl alcohol, 1,4-dioxane, 1,2-dimethoxyethane, acetic acid, ethyl acetate, water, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, N. , N-dimethylformamide, toluene, n-hexane, etc., or a mixed solvent thereof, using lane nickel, hydrogen, ammonium formate, etc., can be carried out from 0 ° C. to room temperature, and in some cases, by heating and refluxing. If necessary, catalysts such as palladium carbon, rhodium carbon, platinum carbon, palladium hydroxide, and platinum oxide can be added. Further, if necessary, an acid such as trifluoroacetic acid can be added as a reaction accelerator.
Alternatively, trifluoroacetic acid, p-toluenesulfonic acid, sulfuric acid, hydrogen chloride, hydrobromide, trifluoride in dichloromethane, chloroform, 1,4-dioxane, tetrahydrofuran, toluene, benzene, water, etc., or a mixed solvent thereof. It can be carried out by adding an acid such as boron diethyl ether complex, boron tribromide, aluminum chloride, and heating at −78 ° C. to reflux. If necessary, anisole, pentamethylbenzene, dimethyl sulfide and the like can be added as a reaction accelerator.

[Synthetic pathway 8]
When the above-mentioned compound (2) is represented by the compound (2 g), for example, it is produced according to the method described in detail in the following synthetic route 8 or a method similar thereto, or other methods described in the literature or a method similar thereto. can do.

(In the formula, R ³⁸ represents a hydrogen atom or a C ₁ to C ₆ alkyl group, PG, R ² , R ³ , R ⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ²² , R ²³ , Ring B. , V, m and q are synonymous with those described above.)

Process 8-1
Compound (2 g) can be produced by removing the protecting group of compound (25).
When the PG is a tert-butoxycarbonyl group as the reaction conditions, the same method as in Step 3-2 can be used.

[Synthetic pathway 9]
When the above-mentioned compound (2) is represented by the compound (2h), for example, it is produced according to the method described in detail in the following synthetic route 9 or a method similar thereto, or other methods described in the literature or a method similar thereto. can do.

(In the equation, c independently represents an integer of 0 to 3, and PG, R ² , R ³ , R ⁴ , R ¹⁵ , R ¹⁶ and m are synonymous with those described above.)

Process 9-1
Compound (2h) can be produced by removing the protecting group of compound (26).
When the PG is a tert-butoxycarbonyl group as the reaction conditions, the same method as in Step 3-2 can be used.

[Synthetic pathway 10]
When the above-mentioned compound (2) is represented by the compound (2i), for example, it is produced according to the method described in detail in the following synthetic route 10 or a method similar thereto, or other methods described in the literature or a method similar thereto. can do.

(In the formula, d is an integer of 0 to 3 independently, and A, PG, R ² , R ³ , R ⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ²² , R ²³ , Ring B. , V, m and q are synonymous with those described above.)

Process 10-1
Compound (2i) can be produced by removing the protecting group of compound (27).
When the PG is a tert-butoxycarbonyl group as the reaction conditions, the same method as in Step 3-2 can be used.

[Synthetic pathway 11]
When the above-mentioned compound (2) is represented by compound (2j), for example, it is produced according to the method described in detail in the following synthetic route 11 or a method similar thereto, or other methods described in the literature or a method similar thereto. can do.

(In the equation, e is an integer of 0 to 3 independently, A, PG, R ² , R ³ , R ⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ²² , R ²³ , Ring B. , V, m, and q are synonymous with those described above.)

Process 11-1
Compound (2j) can be produced by removing the protecting group of compound (28).
When the PG is a tert-butoxycarbonyl group as the reaction conditions, the same method as in Step 3-2 can be used.

[Synthetic pathway 12]
When the above-mentioned compound (2) is represented by the compound (2k), for example, it is produced according to the method described in detail in the following synthetic route 12 or a method similar thereto, or other methods described in the literature or a method similar thereto. can do.

(In the formula, f is an integer of 0 to 3 independently, and PG, R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , Ring A, Y, and n are synonymous with those described above. is there.)

Process 12-1
Compound (2k) can be produced by removing the protecting group of compound (29).
When the PG is a tert-butoxycarbonyl group as the reaction conditions, the same method as in Step 3-2 can be used.

[Synthetic pathway 13]
When the above-mentioned compound (2) is represented by the compound (2l), for example, it is produced according to the method described in detail in the following synthetic route 13 or a method similar thereto, or other methods described in the literature or a method similar thereto. can do.

(In the formula, R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , Ring A, Y, Z and n are synonymous with those described above.)

Process 13-1
Compound (2 l) can be produced by reducing the nitro group of compound (30).
As the reaction conditions, the same method as in Step 6-1 can be carried out.

[Synthetic pathway 14]
When the above-mentioned compound (7) is represented by the compound (7a), for example, it is produced according to the method described in detail in the following synthetic route 14 or a method similar thereto, or other methods described in the literature or a method similar thereto. can do.

(In the formula, R ¹⁷ , R ¹⁸ , R ²⁰ , R ²¹ , R ²² , R ²³ , Ring B, V, Q, r and q are synonymous with those described above.)

Process 14-1
Compound (7a) can be produced by reducing the nitro group of compound (31).
As the reaction conditions, the same method as in Step 6-1 can be carried out.

[Synthetic pathway 15]
When the above-mentioned compound (31) is represented by the compound (31a) or the compound (31b), for example, the method described in detail in the following synthetic route 15 or a method similar thereto, or other methods described in the literature or the same. It can be manufactured according to the same method.

(In the formula, g is an integer of 0 to 3 independently, and R ³⁹ and R ⁴⁰ independently represent a hydrogen atom or a C ₁ to C ₆ alkyl group, respectively, and A, PG, R ¹⁷ , and R ^{18 respectively.} , R ²² , R ²³ , RingB, V, Q and q are synonymous with those described above.)

Process 15-1
Compound (31a) can be produced by reacting compound (32) with compound (33).
The reaction conditions include acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, 1,4-dioxane, tetrahydrofuran, dimethyl sulfoxide, etc., or a compound (33) in a mixed solvent thereof. ) Is added, and it can be carried out from 0 ° C. to heating and reflux. If necessary, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, triethylamine, N, N-diisopropylethylamine, pyridine, 1,8-diazabicyclo [5.4.0] -7-undecene, sodium hydride , N-Butyllithium and the like can be added.

Process 15-2
Compound (35) can be produced by reacting compound (32) with compound (34).
As the reaction conditions, it can be carried out in the same manner as in Step 15-1.

Process 15-3
Compound (36) can be produced by removing the protecting group of compound (35).
When the PG is a tert-butoxycarbonyl group as the reaction conditions, the same method as in Step 3-2 can be used.

Process 15-4
Compound (31b) can be produced by reacting compound (36) with compound (37).
As the reaction conditions, it can be carried out in the same manner as in Step 7-1.

[Synthetic pathway 16]
When the above-mentioned compound (31) is represented by the compound (31c), for example, it is produced according to the method described in detail in the following synthetic route 16 or a method similar thereto, or other methods described in the literature or a method similar thereto. can do.

(In the formula, R ⁴¹ and R ⁴² independently represent a hydrogen atom, a C ₁ to C ₆ alkyl group or a halo C ₁ to C ₆ alkyl group, and R ⁴¹ and R ⁴² bond with each other to form a ring. LG, R ¹⁷ , R ¹⁸ , R ²⁰ , R ²¹ , R ²² , R ²³ , Ring B, V, r and q are synonymous with those described above.)

Process 16-1
Compound (39) can be produced by converting the hydroxyl group of compound (38) into an appropriate leaving group (LG).
As the reaction conditions, it can be carried out in the same manner as in Step 4-1.

Process 16-2
Compound (31c) can be produced by reacting compound (39) with compound (40).
As the reaction conditions, it can be carried out in the same manner as in Step 4-2.

[Synthetic pathway 17]
When the above-mentioned compound (7) is represented by the compound (7b), for example, it is produced according to the method described in detail in the following synthetic route 17 or a method similar thereto, or other methods described in the literature or a method similar thereto. can do.

(In the formula, LG, R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ²⁰ , R ²¹ , R ²² , R ²³ , Ring B, V, Q, m, r and q are synonymous with those described above. )

Process 17-1
Compound (42) can be produced by converting the hydroxyl group of compound (41) into an appropriate leaving group (LG).
As the reaction conditions, it can be carried out in the same manner as in Step 4-1.

Process 17-2
Compound (43) can be produced by azide compound (42).
As the reaction conditions, general azide reaction conditions can be applied. For example, water, dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, tetrahydrofuran, 1,4-dioxane, acetonitrile, acetone, ethanol, methanol and the like, or a mixture thereof. An azidizing agent such as sodium azide or trimethylsilyl azide can be added to the solvent, and the process can be carried out at −78 ° C. to heated reflux. Further, if necessary, tetra-n-butylammonium fluoride (TBAF), boron trifluoride diethyl ether complex, aluminum chloride and the like can be added as a reaction accelerator.

Process 17-3
Compound (7b) can be produced by reducing the azide group of compound (43).
As the reaction conditions, general azide group reduction reaction conditions can be applied. For example, water, tetrahydrofuran, 1,4-dioxane, diethyl ether, ethanol, methanol, dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, acetonitrile, acetone, ethyl acetate. Etc., or in a mixed solvent thereof, a reducing agent such as lithium aluminum hydride, triphenylphosphine, hydrogen, etc. can be added, and the mixture can be carried out at −78 ° C. to heated reflux. Further, if necessary, catalysts such as palladium carbon, rhodium carbon, platinum carbon, palladium hydroxide, and platinum oxide can be added.

[Synthetic pathway 18]
When the above-mentioned compound (7) is represented by the compound (7c), for example, it is produced according to the method described in detail in the following synthetic route 18 or a method similar thereto, or other methods described in the literature or a method similar thereto. can do.

(In the formula, R ⁴³ and R ⁴⁴ each independently represent a hydrogen atom or a C ₁ to C ₆ alkyl group (the C ₁ to C ₆ alkyl groups are _{substituted with one or more C 1} to C ₆ alkyl amino groups, respectively). R ⁴³ and R ⁴⁴ may combine with each other to form a ring, LG, PG, R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ²⁰ , R ²¹ , R ²² , R. ²³ , RingB, V, m, r and q are synonymous with those described above.)

Process 18-1
Compound (45) can be produced by converting the hydroxyl group of compound (44) into an appropriate leaving group (LG).
As the reaction conditions, it can be carried out in the same manner as in Step 4-1.

Process 18-2
Compound (47) can be produced by reacting compound (45) with compound (46).
As the reaction conditions, it can be carried out in the same manner as in Step 4-2.

Process 18-3
Compound (7c) can be produced by removing the protecting group of compound (47).
When the PG is a tert-butoxycarbonyl group as the reaction conditions, the same method as in Step 3-2 can be used.

[Synthetic pathway 19]
When the above-mentioned compound (7) is represented by the compound (7d), for example, it is produced according to the method described in detail in the following synthetic route 19 or a method similar thereto, or other methods described in the literature or a method similar thereto. can do.

Process 19-1
Compound (7d) can be produced by subjecting compound (48) to a Curtius rearrangement reaction.
As the reaction conditions, general Curtius rearrangement reaction conditions can be applied. For example, in toluene, benzene, diphenyl ether, tetrahydrofuran, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, etc., or a mixed solvent thereof, an azidizing agent such as diphenylphosphate azide. , Sodium azide and the like, and bases such as triethylamine and pyridine are added and reacted at 0 ° C. to heating and refluxing, and then water and the like are added and the reaction can be carried out from 0 ° C. to heating and refluxing. Further, if necessary, an acid such as hydrogen chloride can be added as a reaction accelerator.

[Synthetic pathway 20]
When the above-mentioned compound (7) is represented by the compound (7e), for example, it is produced according to the method described in detail in the following synthetic route 20 or a method similar thereto, or other methods described in the literature or a method similar thereto. can do.

(In the equation, h is an integer of 0 to 3, R ⁴⁵ and R ⁴⁶ independently represent a hydrogen atom or a C ₁ to C ₆ alkyl group, respectively, and R ⁴⁵ and R ⁴⁶ bond with each other to form a ring. R ¹⁷ and R ¹⁸ may be synonymous with those described above.)

Process 20-1
Compound (51) can be produced by reacting compound (49) with compound (50).
As the reaction conditions, it can be carried out in the same manner as in Step 7-1.

Process 20-2
Compound (7e) can be produced by reducing compound (51).
As reaction conditions, no solvent, or water, tetrahydrofuran, 1,4-dioxane, diethyl ether, ethanol, methanol, dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, Triethylsilane, sodium borohydride triacetoxyboronate, sodium borohydride, sodium borohydride, lithium borohydride, borane-dimethylsulfide complex, hydrogen in acetonitrile, acetone, ethyl acetate, dichloromethane, etc., or a mixed solvent thereof. It can be carried out by adding a reducing agent such as lithium aluminum or hydrogen and heating at −78 ° C. to reflux. If necessary, an acid such as trifluoroacetic acid, acetic acid, boron trifluoride diethyl ether complex, and a catalyst such as palladium carbon, rhodium carbon, platinum carbon, palladium hydroxide, and platinum oxide can be added.

[Synthetic pathway 21]
When the above-mentioned compound (7) is represented by the compound (7f), for example, it is produced according to the method described in detail in the following synthetic route 21 or a method similar thereto, or other methods described in the literature or a method similar thereto. can do.

^(Wherein, PG, RingB, ^{R 17} and ^{R 18} have the same meanings as those described above.)

Process 21-1
Compound (53) can be produced by protecting the amino group of compound (52).
As reaction conditions, when PG is a tert-butoxycarbonyl group, dichloromethane, 1,4-dioxane, tetrahydrofuran, toluene, ethyl acetate, water, etc., or a mixed solvent thereof, di-tert-butyl dicarbonate, etc. are added. , -78 ° C. to room temperature, and in some cases, heating and refluxing. If necessary, bases such as triethylamine, N, N-diisopropylethylamine, potassium carbonate, and sodium carbonate can be added. Further, if necessary, a reaction accelerator such as pyridine, N, N-dimethyl-4-aminopyridine can be added.

Process 21-2
Compound (7f) can be produced by reducing the nitro group of compound (53).
As the reaction conditions, the same method as in Step 6-1 can be carried out.

[Synthetic pathway 22]
When the above-mentioned compound (7) is represented by the compound (7 g), for example, it is produced according to the method described in detail in the following synthetic route 22 or a method similar thereto, or other methods described in the literature or a method similar thereto. can do.

(In the formula, i independently represents an integer of 0 to 3, and PG, LG, R ²² , R ²³ , q and Q are synonymous with those described above.)

Process 22-1
Compound (57) can be produced by reacting compound (55) with compound (56).
As the reaction conditions, it can be carried out in the same manner as in Step 4-2.

Process 22-2
Compound (7 g) can be produced by removing the protecting group of compound (57).
When the PG is a tert-butoxycarbonyl group as the reaction conditions, the same method as in Step 3-2 can be used.

[Synthetic pathway 23]
When the above-mentioned compound (7) is represented by the compound (7h), for example, it is produced according to the method described in detail in the following synthetic route 23 or a method similar thereto, or other methods described in the literature or a method similar thereto. can do.

(In the formula, LG, R ¹⁷ , R ¹⁸ , R ²⁰ , R ²¹ , R ²² , R ²³ , Ring B, r, q and Q are synonymous with those described above.)

Process 23-1
Compound (59) can be produced by reacting compound (58) with compound (56).
As reaction conditions, dichloromethane, 1,2-dichloroethane, benzene, toluene, tetrahydrofuran, N, N-dimethylformamide, 1,4-dioxane, acetonitrile and the like, or a mixed solvent thereof, compound (56) or a salt thereof and the like. Can be added and carried out at −78 ° C. to heating reflux. If necessary, sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, N, N-diisopropylethylamine, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), Alternatively, a base such as 1,5-diazabicyclo [4.3.0] nona-5-ene (DBN) can be added.

Process 23-2
Compound (7h) can be produced by amifying compound (59).
Reaction conditions include 1,2-dimethoxyethane, 1,4-dioxane, toluene, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, acetonitrile and the like, or benzophenoneimine and the like in a mixed solvent thereof. Add an aminating agent, add a base such as potassium carbonate, tripotassium phosphate, sodium carbonate, cesium carbonate, potassium acetate, or triethylamine, and add tris (dibenzylideneacetone) dipalladium (0) (Pd ₂ (dba) _3). ), Palladium acetate (Pd (OAc) ₂ ), bis (triphenylphosphine) palladium (II) dichloride (PdCl ₂ (Ph ₃ P) ₂ ), [1,1'-bis (diphenylphosphino) ferrocene] palladium ( II) Dichloride (PdCl ₂ (dppf)), Tetrakis (triphenylphosphine) palladium (Pd (Ph ₃ P) ₄ ), or (2-dicyclohexylphosphino-2', 4', 6'-triisopropylbiphenyl) amino Palladium catalysts such as biphenylpalladium chloride (XPhos Pd G3) and, if necessary, 2-di-tert-butylphosphino-2', 4', 6'-triisopropylbiphenyl (tert-BuXPhos), 2-dicyclohexyl. Phosphino-2', 6'-dimethoxybiphenyl (SPhos), 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (BINAP), 4,5-bis (diphenylphosphino) -9, After adding a ligand such as 9-dimethylxanthene (XantPhos) and reacting at room temperature to heating / reflux, an acidic aqueous solution such as hydrochloric acid is added, and the reaction can be carried out at −78 ° C. to heating / reflux.

[Synthetic pathway 24]
When the above-mentioned compound (7) is represented by the compound (7i), for example, it is produced according to the method described in detail in the following synthetic route 24 or a method similar thereto, or other methods described in the literature or a method similar thereto. can do.

(In the formula, R ⁴⁷ represents a hydrogen atom or a C ₁ to C ₆ alkyl group, and PG, R ⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , Ring B and m are synonymous with those described above.)

Process 24-1
Compound (62) can be produced by reducing the cyano group of compound (61).
As the reaction conditions, general cyano group reduction conditions can be used. For example, methanol, ethanol, isopropyl alcohol, 1,4-dioxane, 1,2-dimethoxyethane, acetic acid, water, tetrahydrofuran, diethyl ether, tert-butylmethyl ether, N, N-dimethylformamide, toluene, n-hexane and the like. , Or a reducing agent such as lane nickel, formic acid, sodium borohydride, nickel borohydride, cobalt hydride, or lithium aluminum hydride is added to the solvent, and the mixture is heated at 0 ° C. to room temperature, and in some cases, heated and refluxed. Can be done at. Alternatively, methanol, ethanol, isopropyl alcohol, 1,4-dioxane, 1,2-dimethoxyethane, acetic acid, ethyl acetate, water, tetrahydrofuran, tert-butylmethyl ether, N, N-dimethylformamide, toluene and the like, or theirs. It is also possible to reduce by adding a catalyst such as palladium carbon, rhodium carbon, platinum carbon, or platinum oxide in a mixed solvent under a hydrogen atmosphere.

Process 24-2
Compound (64) can be produced by reducing alkylating compound (62) with compound (63).
The reaction conditions include dichloromethane, 1,2-dichloroethane, chloroform, 1,4-dioxane, tetrahydrofuran, toluene, benzene, methanol, ethanol and the like, or in a mixed solvent thereof, the aldehyde represented by compound (63), or the like. Compounds such as paraformaldehyde, formalin aqueous solution, glycolaldehyde dimer, etc. are added to add sodium borohydride, sodium borohydride, sodium borohydride, lithium borohydride, borane-dimethylsulfide complex, lithium aluminum hydride, etc. Alternatively, it can be carried out by adding a reducing agent such as 2-picorylborane and heating at −78 ° C. to room temperature, and in some cases, heating and refluxing. Alternatively, methanol, ethanol, isopropyl alcohol, 1,4-dioxane, 1,2-dimethoxyethane, ethyl acetate, water, tetrahydrofuran, tert-butylmethyl ether, N, N-dimethylformamide, toluene, etc., or a mixed solvent thereof. In a medium or hydrogen atmosphere, a catalyst such as palladium carbon, rhodium carbon, platinum carbon, or platinum oxide can be added for reduction. If necessary, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, boron trifluoride diethyl ether complex, boron tribromide, aluminum chloride, chlorotrimethylsilane, 2,2,2-trifluoroethanol, tetra orthotitanium acid A reaction accelerator such as isopropyl can be added.

Process 24-3
Compound (7i) can be produced by removing the protecting group of compound (64).
When the PG is a tert-butoxycarbonyl group as the reaction conditions, the same method as in Step 3-2 can be used.

[Synthetic pathway 25]
The above-mentioned compound (4a) can be produced, for example, according to the method described in detail in the following synthetic route 25 or a method similar thereto, or any other method described in the literature or a method similar thereto.

(In the formula, R ⁴⁸ represents a C ₁ to C ₆ alkyl group, and R ² has the same meaning as described above.)

Process 25-1
Compound (4a) can be produced by hydrolyzing compound (65).
As the reaction conditions, it can be carried out in the same manner as in Step 1-2.

[Synthetic pathway 26]
When the above-mentioned compound (65) is represented by the compound (65a) or the compound (65b), for example, the method described in detail in the following synthetic route 26 or a method similar thereto, or other methods described in the literature or the same. It can be manufactured according to the same method.

(In the formula, R ⁵⁰ represents a C ₁ to C ₆ alkyl group, and R ^2a , R ^2d and R ^2e are synonymous with those described above.)

Process 26-1
Compound (67) can be produced by oximeizing compound (66).
As reaction conditions, add water, tetrahydrofuran, diethyl ether, dichloromethane, ethyl acetate, etc., or a mixed solvent thereof, sodium nitrite, isoamyl nitrite, etc., and carry out the reaction at −78 ° C. to room temperature, and in some cases, heating under reflux. Can be done. If necessary, an acid such as acetic acid or hydrogen chloride can be added.

Process 26-2
Compound (65a) can be produced by reacting compound (67) with compound (68).
As a reaction condition, zinc powder or the like is added in a solvent such as acetic acid, and the reaction can be carried out from 0 ° C. to heating under reflux. Sodium acetate and the like can be added as needed.

Process 26-3
Compound (65b) can be produced by reducing the carbonyl group of compound (65a).
As reaction conditions, a reducing agent such as sodium borohydride is added to 1,4-dioxane, tetrahydrofuran, diethyl ether, etc., or a mixed solvent thereof, and the reaction is carried out at −78 ° C. to room temperature, and in some cases, heating under reflux. Can be done. If necessary, a reaction accelerator such as boron trifluoride diethyl ether complex can be added.

[Synthetic pathway 27]
When the above-mentioned compound (65) is represented by the compound (65c), for example, it is produced according to the method described in detail in the following synthetic route 27 or a method similar thereto, or other methods described in the literature or a method similar thereto. can do.

(In the formula, R ⁵² represents a C ₁ to C ₆ alkyl group, R ⁵³ represents a hydrogen atom, a C ₁ to C ₆ alkyl group, or a C ₂ to C ₆ alkenyl group, and R ⁵³ and Z are bonded to each other. X, R ⁶ , R ⁷ , R ⁸ , Ring A, n and Z are synonymous with those described above.)

Process 27-1
Compound (65c) can be produced by reacting compound (69) with compound (70).
The reaction conditions include tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, toluene, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, ethanol, etc., or a mixed solvent thereof. Compound (70) can be added and the mixture can be carried out from room temperature to heating and reflux. If necessary, bases such as potassium carbonate, tripotassium phosphate, sodium carbonate, cesium carbonate, potassium acetate, or triethylamine, tris (dibenzylideneacetone) dipalladium (0) (Pd ₂ (dba) ₃ ), palladium acetate (Pd (OAc) ₂ ), bis (triphenylphosphine) palladium (II) dichloride (PdCl ₂ (Ph ₃ P) ₂ ), [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride ( PdCl ₂ (dppf)), tetrakis (triphenylphosphine) palladium (Pd (Ph ₃ P) ₄ ), or (2-dicyclohexylphosphino-2', 4', 6'-triisopropylbiphenyl) aminobiphenylpalladium chloride ( Palladium catalysts such as XPhos Pd G3), 2-di-tert-butylphosphino-2', 4', 6'-triisopropylbiphenyl (tert-BuXPhos), 2-dicyclohexylphosphino-2', 6' -Dimethoxybiphenyl (SPhos), 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (BINAP), or 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (XantPhos) And other ligands can be added.

[Synthetic pathway 28]
When the above-mentioned compound (65) is represented by the compound (65d), for example, it is produced according to the method described in detail in the following synthetic route 28 or a method similar thereto, or other methods described in the literature or a method similar thereto. can do.

(In the formula, R ⁵⁴ represents a C ₁ to C ₆ alkyl group, and LG, R ⁶ , R ⁷ , R ⁸ , Ring A, n, and Z are synonymous with those described above.)

Process 28-1
Compound (65d) can be produced by reacting compound (71) with compound (72).
As the reaction conditions, it can be carried out in the same manner as in Step 23-1.

[Synthetic pathway 29]
When the above-mentioned compound (65) is represented by the compound (65e), for example, it is produced according to the method described in detail in the following synthetic route 29 or a method similar thereto, or other methods described in the literature or a method similar thereto. can do.

(In the formula, R ⁵⁵ represents a C ₁ to C ₆ alkyl group, and R ⁵⁶ and R ⁵⁷ each independently represent a hydrogen atom or a C ₁ to C ₆ alkyl group (the C ₁ to C ₆ alkyl groups are C). ₁ to C ₆ alkylamino groups may be substituted one or more), R ⁵⁶ and R ⁵⁷ may be bonded to each other to form a ring, and R ⁶ , R ⁷ , R ⁸ , Ring A and n It is synonymous with the above.)

Process 29-1
Compound (65e) can be produced by reducing alkylating compound (73) with compound (74).
As the reaction conditions, it can be carried out in the same manner as in Step 7-1.

[Synthetic pathway 30]
When the above-mentioned compound (65) is represented by the compound (65f), for example, it is produced according to the method described in detail in the following synthetic route 30 or a method similar thereto, or other methods described in the literature or a method similar thereto. can do.

(In the formula, R ⁵⁸ represents a hydrogen atom or a C ₁ to C ₆ alkyl group, and R ⁵⁸ may be bonded to each other to form a ring, X, R ⁶ , R ⁷ , R ⁸ , R ⁵² , Ring A. , N and Z are synonymous with those described above.)

Process 30-1
Compound (65f) can be produced by subjecting compound (69) and compound (75) to a coupling reaction.
As the reaction conditions, general Suzuki-Miyaura coupling reaction conditions can be applied. For example, compound (75) is added in dimethylsulfoxide, N, N-dimethylformamide, 1,4-dioxane, toluene, tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, water, etc., or a mixed solvent thereof. , Potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, tripotassium phosphate, cesium fluoride, triethylamine, or bases such as N, N-diisopropylethylamine, and bis (triphenylphosphine) palladium ( II) Dichloride (PdCl ₂ (PPh ₃ ) ₂ ), [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (PdCl ₂ (dppf) · CH ₂ Cl ₂ ), [1, 1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride (PdCl ₂ (dppf)), tetrakis (triphenylphosphine) palladium (Pd (Ph ₃ P) ₄ ), palladium acetate (Pd (OAc) ₂ ) , Tris (dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ ), 2-dicyclohexylphosphino-2', 4', 6'-triisopropylbiphenyl) aminobiphenyl palladium chloride (XPhos Pd G3) and other palladium catalysts. It can be carried out from 0 ° C. to heating and refluxing. Also, if necessary, 2-di-tert-butylphosphino-2', 4', 6'-triisopropylbiphenyl (tert-BuXPhos), 2-dicyclohexylphosphino-2', 6'-dimethoxybiphenyl (SPhos) ) Etc. can be added.

[Synthetic pathway 31]
When the above-mentioned compound (65) is represented by the compound (65 g) or the compound (65 h), for example, the method described in detail in the following synthetic route 31 or a method similar thereto, or other methods described in the literature or the same. It can be manufactured according to the same method.

(In the formula, j independently represents an integer of 0 to 3, and R ⁵⁹ is a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a benzyl group, an acetyl group, a benzoyl group or a 9-fluorenylmethyloxycarbonyl group. Such as a protecting group such as, or a C ₁ to C ₆ alkyl group, R ⁶⁰ represents a hydrogen atom or a C ₁ to C ₆ alkyl group, and R ⁶⁰ may be bonded to each other to form a ring, and X and R may be formed. ⁶ , R ⁷ , R ⁸ , R ⁵² , Ring A and n are synonymous with those described above.)

Process 31-1
Compound (65 g) can be produced by subjecting compound (69) and compound (76) to a coupling reaction.
As the reaction conditions, it can be carried out in the same manner as in Step 30-1.

Process 31-2
Compound (65 h) can be produced by reducing the unsaturated bond of compound (65 g).
Reaction conditions include methanol, ethanol, isopropyl alcohol, 1,4-dioxane, 1,2-dimethoxyethane, ethyl acetate, water, tetrahydrofuran, tert-butylmethyl ether, N, N-dimethylformamide, toluene and the like, or theirs. It can be carried out in a mixed solvent under a hydrogen atmosphere by adding a catalyst such as palladium carbon, rhodium carbon, platinum carbon or platinum oxide and heating at 0 ° C. to reflux. If necessary, acetic acid, trifluoroacetic acid, 2,2,2-trifluoroethanol and the like can be added as a reaction accelerator.

[Synthetic pathway 32]
When the above-mentioned compound (65) is represented by the compound (65i), for example, it is produced according to the method described in detail in the following synthetic route 32 or a method similar thereto, or other methods described in the literature or a method similar thereto. can do.

(In the equation, X, R ⁶ , R ⁷ , R ⁸ , R ⁵² , Ring A and n are synonymous with those described above.)

Process 32-1
Compound (78) can be produced by subjecting compound (69) and compound (77) to a coupling reaction.
As the reaction conditions, it can be carried out in the same manner as in Step 30-1.

Process 32-2
Compound (65i) can be produced by reducing the unsaturated bond of compound (78).
As the reaction conditions, the same method as in Step 31-2 can be used.

[Synthetic pathway 33]
When the above-mentioned compound (65) is represented by the compound (65j), for example, it is produced according to the method described in detail in the following synthetic route 33 or a method similar thereto, or other methods described in the literature or a method similar thereto. can do.

(In the formula, R ⁶¹ represents a C ₁ to C ₆ alkyl group, and R ⁸ , Y, Z are synonymous with those described above.)

Process 33-1
Compound (81) can be produced by reacting compound (79) with compound (80).
As reaction conditions, compound (80) is added in methanol, ethanol, 1-propanol, isopropyl alcohol, tetrahydrofuran, 1,4-dioxane, toluene, N, N-dimethylformamide, etc., or a mixed solvent thereof, and the temperature is adjusted to room temperature. It can be carried out by heating and refluxing.

Process 33-2
Compound (65j) can be produced by dehydrating compound (81).
As reaction conditions, an acid such as paratoluenesulfonic acid or camphorsulfonic acid can be added to benzene, toluene, xylene or the like, or a mixed solvent thereof, and the reaction can be carried out at room temperature to heating with reflux.

[Synthetic pathway 34]
When the above-mentioned compound (3) is represented by the compound (3a), or when the above-mentioned compound (9) is represented by the compound (9a), for example, the method described in detail in the following synthetic route 34 or a method thereof. It can be produced according to the same method, other methods described in the literature, or a method similar thereto.

(In the formula, R ⁶² represents a C ₁ to C ₆ alkyl group, and LG, PG and R ³ are synonymous with those described above.)

Process 34-1
Compound (83) can be produced by converting the hydroxyl group of compound (82) into an appropriate leaving group (LG).
As the reaction conditions, it can be carried out in the same manner as in Step 4-1.

Process 34-2
Compound (85) can be produced by reacting compound (84) with compound (83).
As reaction conditions, compound (83) is added to N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, etc., or a mixed solvent thereof, and the reaction is carried out at 0 ° C. to reflux by heating. be able to. If necessary, sodium hydride, tert-butoxypotassium, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] nona-5 -Bases such as ene (DBN) can be added.

Process 34-3
Compound (86) can be produced by hydrolyzing compound (85).
As the reaction conditions, it can be carried out in the same manner as in Step 1-2.

Process 34-4
Compound (87) can be produced by decarboxylating compound (86).
As the reaction conditions, benzene, toluene, xylene, 1,2-dichlorobenzene, dimethyl sulfoxide and the like, or a mixed solvent thereof, can be carried out at room temperature to heated reflux. If necessary, hydrogen chloride, paratoluenesulfonic acid and the like can be added as a reaction accelerator.

Process 34-5
Compound (9a) can be produced by hydrolyzing compound (87).
As the reaction conditions, it can be carried out in the same manner as in Step 1-2.

Process 34-6
Compound (87) can be produced by esterifying compound (9a).
As reaction conditions, methanol, diethyl ether, tetrahydrofuran, n-hexane, benzene, toluene and the like, or trimethylsilyldiazomethane or the like in a mixed solvent thereof is added, and the reaction can be carried out at 0 ° C. to room temperature.

Process 34-7
Compound (3a) can be produced by removing the protecting group of compound (87).
When the PG is a tert-butoxycarbonyl group as the reaction conditions, the same method as in Step 3-2 can be used.

[Synthetic pathway 35]
When the above-mentioned compound (3) is represented by the compound (3b), and when the above-mentioned compound (9) is represented by the compound (9b), for example, the method described in detail in the following synthetic route 35 or the like. It can also be produced according to the above method, other methods described in the literature, or a method similar thereto.

(In the formula, LG, PG and R ³ are synonymous with those described above.)

Process 35-1
Compound (89) can be produced by reacting compound (88) with compound (83).
As reaction conditions, compound (83) is added in tetrahydrofuran, n-hexane or the like, or a mixed solvent thereof, and a base such as n-butyllithium is added, and the reaction can be carried out at −78 ° C. to room temperature.

Process 35-2
Compound (3b) can be produced by hydrolyzing compound (89).
As reaction conditions, hydrogen chloride or the like can be added to water, tetrahydrofuran, 1,4-dioxane or the like, or a water-containing mixed solvent thereof, so that the reaction can be carried out at 0 ° C. to reflux by heating.

Process 35-3
Compound (90) can be produced by protecting the amino group of compound (3b).
As a reaction condition, when PG is a tert-butoxycarbonyl group, it can be carried out in the same manner as in Step 21-1.

Process 35-4
Compound (9b) can be produced by hydrolyzing compound (90).
As the reaction conditions, it can be carried out in the same manner as in Step 1-2.

[Synthetic pathway 36]
When the above-mentioned compound (10) is represented by the compound (10a), for example, it is produced according to the method described in detail in the following synthetic route 36 or a method similar thereto, or other methods described in the literature or a method similar thereto. can do.

(In the formula, X, PG, R ³ , R ⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , Ring B and m are synonymous with those described above.)

Process 36-1
Compound (93) can be produced by subjecting compound (91) and compound (92) to a coupling reaction.
As the reaction conditions, it can be carried out in the same manner as in Step 30-1.

Process 36-2
Compound (10a) can be produced by reducing the unsaturated bond of compound (93).
As the reaction conditions, the same method as in Step 31-2 can be used.

[Synthetic pathway 37]
When the above-mentioned compound (10) is represented by the compound (10b), for example, it is produced according to the method described in detail in the following synthetic route 37 or a method similar thereto, or other methods described in the literature or a method similar thereto. can do.

Process 37-1
Compound (10b) can be produced by subjecting compound (91) to a cyanation reaction.
As reaction conditions, a cyanating agent such as zinc cyanide is used in dimethylsulfoxide, N, N-dimethylformamide, 1,4-dioxane, toluene, tetrahydrofuran, 1,2-dimethoxyethane, water, etc., or a mixed solvent thereof. In addition, bis (triphenylphosphine) palladium (II) dichloride (PdCl ₂ (PPh ₃ ) ₂ ), [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (PdCl ₂ (dppf)) CH ₂ Cl ₂ ), [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride (PdCl ₂ (dppf)), tetrakis (triphenylphosphine) palladium (Pd (Ph ₃ P) ₄ ) , Palladium acetate (Pd (OAc) ₂ ), tris (dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ ), or 2-dicyclohexylphosphino-2', 4', 6'-triisopropylbiphenyl) aminobiphenyl It can be carried out from 0 ° C. to heated reflux using a palladium catalyst such as palladium chloride (XPhos Pd G3). Also, if necessary, 2-di-tert-butylphosphino-2', 4', 6'-triisopropylbiphenyl (tert-BuXPhos), or 2-dicyclohexylphosphino-2', 6'-dimethoxybiphenyl ( A ligand such as SPhos) can be used.

[Synthetic pathway 38]
When the above-mentioned compound (10) is represented by the compound (10c), for example, it is produced according to the method described in detail in the following synthetic route 38 or a method similar thereto, or other methods described in the literature or a method similar thereto. can do.

(In the formula, R ⁶³ represents a C ₁ to C ₆ alkyl group, PG, R ³ , R ⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ²⁰ , R ²¹ , R ²² , R ²³ , Ring B, m, r, q, V and Q are synonymous with those described above.)

Process 38-1
Compound (10c) can be produced by reducing compound (94).
As reaction conditions, in methanol, ethanol, tetrahydrofuran, diethyl ether, dichloromethane, toluene, benzene, n-hexane, etc., or a mixed solvent thereof, diisobutylaluminum hydride, lithium aluminum hydride, lithium boron hydride, sodium borohydride, etc. , Sodium bis (2-methoxyethoxy) aluminum sodium (Red-Al), or tri (sec-butyl) boron hydride, using a hydride reducing agent such as lithium boron, can be carried out at −78 ° C. to heated reflux.

[Synthetic pathway 39]
Of the above-mentioned compound (I), R ¹ is a nitrogen atom, R ⁵ is a phenyl group which may be substituted with ^{R 17} , R ¹⁸ and R ¹⁹ ^{, and R 1} and R ⁵ are combined to form a benzimidazole. When represented by a compound forming a ring, that is, compound (98), for example, it is produced according to the method described in detail in the following synthetic route 39 or a method similar thereto, or other methods described in the literature or a method similar thereto. can do.

(In the formula, PG, X, R ² , R ³ , R ⁴ , R ¹⁷ , R ¹⁸ and R ¹⁹ are synonymous with those described above.)

Process 39-1
Compound (96) can be produced by reacting compound (9) with compound (95).
As reaction conditions, compound (95) is added, and after performing a dehydration condensation reaction in the same manner as in Step 1-3, solvent-free, water, 1,4-dioxane, toluene, xylene, ethanol, acetonitrile, etc., or Acetic acid, hydrogen chloride, paratoluenesulfonic acid and the like can be added to the mixed solvent thereof, and the mixture can be carried out at 0 ° C. to heated reflux.

Process 39-2
Compound (97) can be produced by removing the protecting group of compound (96).
When the PG is a tert-butoxycarbonyl group as the reaction conditions, the same method as in Step 3-2 can be used.

Process 39-3
Compound (98) can be produced by amidating compound (97) with compound (4a) or compound (4b).
As reaction conditions, compound (4a), compound (4b), or the like can be added, and the same method as in step 1-1 can be used.

[Synthetic pathway 40]
When the above-mentioned compound (96) is represented by the compound (96a), for example, it is produced according to the method described in detail in the following synthetic route 40 or a method similar thereto, or other methods described in the literature or a method similar thereto. can do.

(In the formula, R ⁶⁴ and R ⁶⁵ independently represent a hydrogen atom, a C ₁ to C ₆ alkyl group or a 3 to 10 membered heterocycloalkyl group (the C ₁ to C ₆ alkyl group and a 3 to 10 membered hetero). The cycloalkyl group may be _{substituted with one or more C 1} to C ₆ alkyl groups or C ₁ to C ₆ alkyl amino groups), and R ⁶⁴ and R ⁶⁵ may be bonded to each other to form a ring. X, PG, R ² , R ³ , R ⁴ , R ¹⁷ , R ¹⁸ , R ²⁰ , R ²¹ and r are synonymous with those described above.)

Process 40-1
Compound (100) can be produced by halogenating compound (99).
Reaction conditions include no solvent, carbon tetrachloride, acetonitrile, etc., or a mixed solvent thereof, a halogenating agent such as N-bromosuccinimide, bromine, 2,2'-azobis (isobutyronitrile), benzoyl peroxide, etc. It can be carried out from room temperature to heating and reflux by adding the radical initiator of. If necessary, light can be irradiated.

Process 40-2
Compound (96a) can be produced by reacting compound (100) with compound (101).
As the reaction conditions, it can be carried out in the same manner as in Step 4-2.

[Synthetic pathway 41]
When the above-mentioned compound (96) is represented by the compound (96b), for example, it is produced according to the method described in detail in the following synthetic route 41 or a method similar thereto, or other methods described in the literature or a method similar thereto. can do.

(In the formula, R ⁶⁶ represents a C ₁ to C ₆ alkyl group, R ⁶⁷ and R ⁶⁸ each independently represent a hydrogen atom or a C ₁ to C ₆ alkyl group, and R ⁶⁷ and R ⁶⁸ are bonded to each other. A ring may be formed, and LG, PG, R ³ and R ⁴ are synonymous with those described above.)

Process 41-1
Compound (103) can be produced by reducing compound (102).
As the reaction conditions, it can be carried out in the same manner as in Step 38-1.

Process 41-2
Compound (104) can be produced by converting the hydroxyl group of compound (103) into an appropriate leaving group (LG).
As the reaction conditions, it can be carried out in the same manner as in Step 4-1.

Process 41-3
Compound (96b) can be produced by reacting compound (104) with compound (105).
As the reaction conditions, it can be carried out in the same manner as in Step 4-2.

[Synthetic pathway 42]
When the above-mentioned compound (98) is represented by the compound (98a), for example, it is produced according to the method described in detail in the following synthetic route 42 or a method similar thereto, or other methods described in the literature or a method similar thereto. can do.

(In the formula, PG ¹ represents a protecting group such as a tert-butoxycarbonyl group or a benzyloxycarbonyl group, and PG ² represents a protecting group such as a benzyl group or a tert-butyldimethylsilyl group, R ^2a , R ^2d , R. ^2e , R ³ , R ¹⁷ , R ¹⁸ , R ²² , R ²³ , Q and q are synonymous with those described above.)

Process 42-1
Compound (107) can be produced by adding a ^{protecting group (PG 1} ) on the nitrogen atom of the pyrrole ring and benzimidazole ring of compound (106).
As a reaction condition, when PG ¹ is a tert-butoxycarbonyl group, it can be carried out in the same manner as in Step 21-1.

Process 42-2
Compound (108) can be produced by removing ^{the protecting group (PG 2} ) on the hydroxyl group of compound (107).
^{When PG 2} is a benzyl group as the reaction conditions, it can be carried out in the same manner as in Step 7-3.

Process 42-3
Compound (110) can be produced by a Mitsunobu reaction between compound (108) and compound (109).
As the reaction conditions, general Mitsunobu reaction conditions can be used. For example, compound (109) is added in a solvent-free solvent, tetrahydrofuran, 1,4-dioxane, toluene, benzene, etc., or a mixed solvent thereof, and phosphorus reagents such as triphenylphosphine, tributylphosphine, and trimethylphosphine, diisopropyl azodicarboxylate, etc. An azo compound such as (DIAD), diethyl azodicarboxylate (DEAD), or 1,1'-azobis (N, N-dimethylformamide) (TMAD) can be added, and the treatment can be carried out from room temperature to heating and reflux.

Process 42-4
Compound (98a) can be produced by removing ^{the protecting group (PG 1} ) on the nitrogen atom of the pyrrole ring and benzimidazole ring of compound (110).
As a reaction condition, when PG ¹ is a tert-butoxycarbonyl group, it can be carried out in the same manner as in Step 3-2.

[Synthetic pathway 43]
When the above-mentioned compound (98) is represented by the compound (98b), for example, it is produced according to the method described in detail in the following synthetic route 43 or a method similar thereto, or other methods described in the literature or a method similar thereto. can do.

(In the formula, PG ³ represents a protecting group such as a tert-butoxycarbonyl group or a benzyloxycarbonyl group, and k independently represents an integer of 0 to 3, A, PG ¹ , R ^2a , R ^2d , R. ^2e , R ³ , R ¹⁷ , R ¹⁸ , R ²² , R ²³ , and q are synonymous with those described above.)

Process 43-1
Compound (112) can be produced by a Mitsunobu reaction between compound (108) and compound (111).
As the reaction conditions, the same method as in Step 42-3 can be used.

Process 43-2
Compound (113) can be produced by removing ^{the protecting group (PG 1} ) on the nitrogen atom of the pyrrole ring and benzimidazole ring of compound (112).
As the reaction conditions, when PG ¹ is a tert-butoxycarbonyl group, it can be carried out in the same manner as in Step 3-2.

Process 43-3
Compound (98b) can be produced by removing ^{the protecting group (PG 3} ) on the amino group of compound (113).
^{When PG 3} is a benzyloxycarbonyl group as the reaction conditions, it can be carried out in the same manner as in Step 3-2.

[Synthetic pathway 44]
When the above-mentioned compound (98) is represented by the compound (98c), for example, it is produced according to the method described in detail in the following synthetic route 44 or a method similar thereto, or other methods described in the literature or a method similar thereto. can do.

(In the formula, PG ¹ , PG ² , R ^2a , R ^2d , R ^2e , R ³ , R ¹⁷ , R ¹⁸ , R ²² , R ²³ and q are synonymous with those described above.)

Process 44-1
Compound (115) can be produced by a Mitsunobu reaction between compound (108) and compound (114).
As the reaction conditions, the same method as in Step 42-3 can be used.

Process 44-2
Compound (116) can be produced by removing ^{the protecting group (PG 2} ) on the hydroxyl group of compound (115).
As reaction conditions, when PG ² is a tert-butyldimethylsilyl group, fluoride is added to water, acetone, dichloromethane, chloroform, 1,4-dioxane, tetrahydrofuran, toluene, benzene, methanol, ethanol, etc., or a mixed solvent thereof. Tetra-n-butylammonium (TBAF), cesium fluoride, tris (dimethylamino) sulfonium (TASF) difluorotrimethylsilicate, trifluoroacetic acid, paratoluenesulfonic acid, sulfuric acid, hydrogen chloride, hydrobromic acid, trifluoride It can be carried out by adding an acid such as boron diethyl ether complex, boron trifluoride, or aluminum chloride, and heating at −78 ° C. to reflux.

Process 44-3
Compound (98c) can be produced by removing ^{the protecting group (PG 1} ) on the nitrogen atom of the pyrrole ring and benzimidazole ring of compound (116).
As a reaction condition, when PG ¹ is a tert-butoxycarbonyl group, it can be carried out in the same manner as in Step 3-2.

[Synthetic pathway 45]
When the above-mentioned compound (98) is represented by the compound (98d), for example, it is produced according to the method described in detail in the following synthetic route 45 or a method similar thereto, or other methods described in the literature or a method similar thereto. can do.

(In the formula, R ⁶⁹ and R ⁷⁰ each independently represent a hydrogen atom, a C ₁ to C ₆ alkyl group or a hydroxy C ₁ to C ₆ alkyl group, and R ⁶⁹ and R ⁷⁰ bond with each other to form a ring. PG ¹ , LG, R ^2a , R ^2d , R ^2e , R ³ , R ¹⁷ , R ¹⁸ , R ²² , R ²³ and q are synonymous with those described above.)

Process 45-1
Compound (118) can be produced by a Mitsunobu reaction between compound (108) and compound (117).
As the reaction conditions, the same method as in Step 42-3 can be used.

Process 45-2
Compound (119) can be produced by removing ^{the protecting group (PG 1} ) on the nitrogen atom of the pyrrole ring and benzimidazole ring of compound (118).
As a reaction condition, when PG ¹ is a tert-butoxycarbonyl group, it can be carried out in the same manner as in Step 3-2.

Process 45-3
Compound (98d) can be produced by reacting compound (119) with compound (120).
Compound (120) is used as the reaction condition, and the reaction can be carried out in the same manner as in Step 4-2.

[Synthetic pathway 46]
^{When R 1} in the above compound (I) is represented by a hydrogen atom, that is, compound (122), for example, the method described in detail in the following synthesis route 46 or a method similar thereto, or other methods. It can be produced according to the method described in the literature or a method similar thereto.

(In the equation, R ² , R ³ , R ⁴ , R ⁵ and X are synonymous with those described above.)

Process 46-1
Compound (121) can be produced by reducing the carbonyl group of compound (11).
As reaction conditions, hydrides such as boron-tetrahydrofuran complex, borane-dimethylsulfide complex, or lithium aluminum hydride in tetrahydrofuran, diethyl ether, methanol, ethanol, dichloromethane, toluene, benzene, n-hexane, etc., or a mixed solvent thereof. It can be carried out from 0 ° C. to heated reflux using a reducing agent.

Process 46-2
Compound (122) can be produced by amidating compound (121) with compound (4a) or compound (4b).
As reaction conditions, compound (4a), compound (4b), or the like can be added, and the same method as in step 1-1 can be used.

The synthetic route shown above is an example of a method for producing the compound (I) of the present embodiment, and the compound (I) of the present embodiment is the method shown above or a method similar thereto, or other methods. It can be produced according to the method described in the literature or a method similar thereto. These manufacturing methods can be modified in various ways to schemes that can be easily understood by those skilled in the art.

If a protecting group is required depending on the type of functional group, it can be carried out by combining the operations of introduction and desorption as appropriate according to a conventional method. Regarding the type, introduction and desorption of protecting groups, for example, Theodra W. et al. Green & Peter G. M. The methods described in "Greene's Protective Groups in Organic Synthesis" edited by Wuts, future edition, Wiley-Interscience, 2006 can be mentioned.

The intermediate used to produce compound (I) of the present embodiment is, if necessary, solvent extraction, crystallization, recrystallization, chromatography, which is a well-known isolation / purification means for those skilled in the art. It can be isolated and purified by imaging, preparative high performance liquid chromatography, etc.
Further, if necessary, the intermediate may not be isolated or purified and may be used as a crude product in the next reaction.

The "G9a inhibitory action" in the present embodiment is an action that inhibits G9a, which is a major enzyme involved in mono and dimethylation (H3K9me1 and H3K9me2) at the 9th lysine residue of histone H3.
Compound (I) of the present embodiment, or a pharmacologically acceptable salt thereof, exhibits strong inhibitory activity, for example, in a G9a inhibitory activity test.
As a result, the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof is a proliferative disease such as cancer, β-globin dysfunction, fibrosis, pain, neurodegenerative disease, Prader-Willi syndrome. , Malaria, viral infections, myopathy, autism, etc. It can be understood that it is useful as a therapeutic agent or a preventive agent thereof.

The drug containing the compound (I) of the present embodiment as an active ingredient can be in various dosage forms depending on the usage. Examples of such dosage forms include powders, granules, fine granules, dry syrups, tablets, capsules, injections, liquids, ointments, suppositories, patches, sublinguals and the like.

These pharmaceuticals can be configured as a pharmaceutical composition containing the compound (I) of the present embodiment as an active ingredient and a pharmaceutically acceptable additive by a method known according to the dosage form. .. Additives contained in the pharmaceutical composition include excipients, disintegrants, binders, lubricants, diluents, buffers, tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, and stables. Examples thereof include an agent and a solubilizing agent. The pharmaceutical composition can be prepared by appropriately mixing the compound (I) of the present embodiment with an additive, or by diluting and dissolving the compound (I) with an additive.

The drug according to this embodiment can be administered systemically or locally orally or parenterally (nasal, pulmonary, intravenous, rectal, subcutaneous, muscular, transdermal, etc.).

(Example)
Hereinafter, the present invention will be described in more detail based on Test Examples, Examples and Reference Examples. Further, since the raw material compound used for producing the compound (I) also contains a novel compound, an example of producing the raw material compound will be described as a reference example. The present invention is not limited to the compounds described in the following examples, and may be changed within a range that does not deviate from the scope of the present invention.

Of the symbols used in each reference example, each example, and each table, ¹ H-NMR means a spectrum measured by proton nuclear magnetic resonance spectroscopy. CDCl ₃ means chloroform-d, DMSO-D ₆ means dimethyl sulfoxide-d ₆ , and CD ₃ OD means methanol-d ₄ . MS (ESI ⁺⁾ and MS (ESI ^-) electrospray ionization method, MS (FI ⁺⁾ is the electric field ionization, MS (FD ⁺⁾ is field desorption ionization, MS (EI ⁺⁾ electron ionization, MS (CI ⁺ ) means mass spectrometric data measured by the chemical ionization method. Room temperature means 1 to 30 ° C.

Under an argon atmosphere, 0 in a solution of 2-chloro-5-nitropyridine (1.00 g) and tert-butyl 3-hydroxyazetidine-1-carboxylate (2.18 g) in tetrahydrofuran (15.0 mL). 55% sodium hydride (550 mg) was gradually added at ° C., and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was added to water, and the mixture was extracted once with ethyl acetate. The extraction layer was washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, and the insoluble material was removed by filtration. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1-2: 1) to tert-butyl 3- (5-nitropyridin-2-yl) oxyazeti. Din-1-carboxylate (1.82 g) was obtained.
^{1 1} H-NMR (CDCl ₃ , 400MHz) δ: 1.45 (9H, s), 3.97-4.04 (2H, m), 4.32-4.40 (2H, m), 5.38-5.47 (1H, m), 6.90 (1H, 1H, d, J = 9.2 Hz), 8.40 (1H, dd, J = 9.2, 2.4 Hz), 9.03 (1H, d, J = 2.4 Hz).
MS (FI ⁺ ): 296.1 [M + H] ⁺

From Reference Example 1-2 below, using the corresponding starting materials and reactants, by the same method as in Reference Example 1-1, the method described in Step 15-1 or Step 15-2, or a method similar thereto. 1-6 was obtained.

5% palladium carbon in a mixed solution of N- (1-methylpiperidin-4-yl) -5-nitropyridin-2-amine (333 mg) in tetrahydrofuran-ethanol (7.04 mL, 1: 1) under an argon atmosphere. After adding (66.6 mg), the mixture was stirred at room temperature for 8 hours under a hydrogen atmosphere. After replacing the inside of the reaction system with an argon atmosphere, the reaction solution was filtered through Celite, and the residue from which the solvent was distilled off was purified by aminoated silica gel column chromatography (ethyl acetate: methanol = 9: 1) and 2-N-. (1-Methylpiperidin-4-yl) pyridine-2,5-diamine (232 mg) was obtained.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.47-1.58 (2H, m), 2.01-2.08 (2H, m), 2.13-2.21 (2H, m), 2.31 (3H, s), 2.78-2.86 (2H, m), 3.19 (2H, brs), 3.49-3.57 (1H, m), 3.96 (1H, d, J = 7.3 Hz), 6.30 (1H, d, J = 8.5 Hz), 6.94 (1H, m) dd, J = 8.5, 3.0 Hz), 7.68 (1H, d, J = 3.0 Hz).
HRMS (ESI ⁺ ): 207.16063 [M + H] ⁺

Using the corresponding starting materials and reactants, the following Reference Examples 2-2 to 2-7 were obtained by the same method as in Reference Example 2-1 and the method described in Step 14-1 or a method similar thereto. ..

Trifluoroacetic acid (3.00 mL) in a solution of tert-butyl 3- (5-nitropyridin-2-yl) oxyazetidine-1-carboxylate (500 mg) in dichloromethane (3.00 mL) at room temperature. Was added and stirred for 1 hour. After distilling off the solvent of the reaction solution under reduced pressure, the residue was used as it was in Reference Example 4 as a trifluoroacetic acid salt of 2- (azetidine-3-yloxy) -5-nitropyridine.

A 37% aqueous formaldehyde solution (0.672) at room temperature in a solution of trifluoroacetate of 2- (azetidine-3-yloxy) -5-nitropyridine, which is a crude product of Reference Example 3, in dichloromethane (10.0 mL). mL) and sodium borohydride triacetoxyboron (897 mg) were added, and the mixture was stirred for 2 hours. After distilling off the solvent of the reaction solution under reduced pressure, the residue was purified by amination silica gel column chromatography (hexane: ethyl acetate = 3: 1 to 0: 1) to 2- (1-methylazetidine-3-). Il) Oxy-5-nitropyridine (142 mg) was obtained.
^{1 1} H-NMR (CDCl ₃ , 400MHz) δ: 2.63 (3H, s), 3.47-3.55 (2H, m), 4.23-4.31 (2H, m), 5.39-5.48 (1H, m), 6.88 (1H, 1H, d, J = 9.1 Hz), 8.40 (1H, dd, J = 9.1, 3.0 Hz), 9.02 (1H, d, J = 3.0 Hz).
MS (ESI ⁺ ): 210.1 [M + H] ⁺

Under an argon atmosphere, 10% palladium carbon (14.0 mg) in an ethanol (6.50 mL) solution of 2- (1-methylazetidine-3-yl) oxy-5-nitropyridine (140 mg) at room temperature. ) Was added, and the mixture was stirred under a hydrogen atmosphere for 1.5 hours, and then hydrogen in the reaction vessel was replaced with argon. After filtering the reaction solution with Celite, the solvent of the filtrate is distilled off under reduced pressure, and the residue is purified by aminoated silica gel column chromatography (ethyl acetate: methanol = 1: 0 to 9: 1). 6- (1-Methylazetidine-3-yl) oxypyridine-3-amine (46.0 mg) was obtained.
^{1 1} H-NMR (CDCl ₃ , 400MHz) δ: 2.39 (3H, s), 3.04-3.11 (2H, m), 3.35 (2H, br s), 3.75-3.82 (2H, m), 5.06-5.15 (1H) , m), 6.58 (1H, d, J = 8.5 Hz), 7.02 (1H, dd, J = 8.5, 3.0 Hz), 7.60 (1H, d, J = 3.0 Hz).
MS (EI ⁺ ): 179.1 [M] ⁺

It was synthesized in the same manner as in Reference Example 80 using 2- (4-nitrophenyl) ethanol.

Under an argon atmosphere, piperidine (0.404 mL) was added to a solution of 2- (4-nitrophenyl) ethyl methanesulfonate (200 mg) in acetonitrile (1.00 mL) at room temperature, and the mixture was stirred for 69 hours. The reaction mixture was added to water and extracted twice with ethyl acetate. The combined extraction layers were washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, and the insoluble material was removed by filtration. After distilling off the solvent under reduced pressure, the residue was purified by aminoated silica gel column chromatography (hexane: ethyl acetate = 9: 1 to 0: 1) to obtain 1- [2- (4-nitrophenyl) ethyl] piperidine ( 191 mg) was obtained.
^{1 1} H-NMR (CDCl ₃ , 400MHz) δ: 1.41-1.51 (2H, m), 1.56-1.65 (4H, m), 2.38-2.52 (4H, m), 2.55-2.61 (2H, m), 2.86- 2.96 (2H, m), 7.36 (2H, d, J = 8.5 Hz), 8.14 (2H, d, J = 8.5 Hz).
MS (FI ⁺ ): 234.1 [M] ⁺

It was synthesized in the same manner as in Reference Example 5 using 1- [2- (4-nitrophenyl) ethyl] piperidine.
^{1 1} H-NMR (DMSO-D ₆ , 400MHz) δ: 1.31-1.39 (2H, m), 1.42-1.51 (4H, m), 2.28-2.41 (6H, m), 2.47-2.54 (2H, m), 4.78 (2H, s), 6.45 (2H, d, J = 8.5 Hz), 6.82 (2H, d, J = 7.9 Hz).
MS (ESI ⁺ ): 205.2 [M + H] ⁺

Potassium carbonate (384 mg) and 1- (bromomethyl) -4-nitrobenzene (200 mg) in an acetonitrile (2.00 mL) solution of 4,4-difluoropiperidine hydrochloride (219 mg) under an argon atmosphere at room temperature. Was added, and the mixture was stirred for 1 hour. The reaction mixture was added to water, and the mixture was extracted twice with ethyl acetate. The combined extraction layers were washed in the order of water and saturated brine, dried over anhydrous sodium sulfate, and the insoluble material was removed by filtration. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 to 1: 1) to 4,4-difluoro-1-[(4-nitrophenyl) methyl]. Piperidine (220 mg) was obtained.
^{1 1} H-NMR (CDCl ₃ , 400MHz) δ: 1.94-2.08 (4H, m), 2.51-2.61 (4H, m), 3.64 (2H, s), 7.51 (2H, d, J = 8.5 Hz), 8.19 (2H, d, J = 8.5 Hz).
MS (EI ⁺ ): 256.1 [M] ⁺

It was synthesized in the same manner as in Reference Example 5 using 4,4-difluoro-1-[(4-nitrophenyl) methyl] piperidine.
^{1 1} H-NMR (CDCl ₃ , 400MHz) δ: 1.90-2.03 (4H, m), 2.45-2.58 (4H, m), 3.43 (2H, s), 3.62 (2H, br s), 6.64 (2H, d) , J = 8.5 Hz), 7.08 (2H, d, J = 8.5 Hz).
MS (EI ⁺ ): 226.1 [M] ⁺

Triphenylphosphine (2.) in a tetrahydrofuran solution (40.7 mL) of tert-butyl N- [2- [4- (hydroxymethyl) phenyl] ethyl] carbamate (2.05 g) under an argon atmosphere under ice-cooling. 35 g) and carbon tetrabromide (2.97 g) were added, and the mixture was stirred at room temperature for 30 minutes. Diethyl ether (50.0 mL) and hexane (50.0 mL) were added to the reaction mixture, and the resulting solid was filtered off with Celite and washed with diethyl ether. The obtained filtrate was concentrated under reduced pressure to obtain tert-butyl N- [2- [4- (bromomethyl) phenyl] ethyl] carbamate. The obtained crude product was used as it was in the next step without further purification.

Sodium azide (636 mg) in N, N-dimethylformamide solution (40.8 mL) of crude tert-butyl N- [2- [4- (bromomethyl) phenyl] ethyl] carbamate under an argon atmosphere. Was added, and the mixture was stirred at room temperature for 17 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the insoluble matter was removed by filtration. After distilling off the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) and tert-butyl N- [2- [4- (azidomethyl) phenyl] ethyl] carbamate (1.85 g). Got
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.43 (9H, s), 2.80 (2H, t, J = 7.3 Hz), 3.33-3.41 (2H, m), 4.31 (2H, s), 4.56 ( 1H, brs), 7.21 (2H, d, J = 7.9 Hz), 7.26 (2H, d, J = 7.9 Hz).
HRMS (FI ⁺ ): 276.15809 [M] ⁺

Under an argon atmosphere, tert-butyl N- [2- [4- (azidomethyl) phenyl] ethyl] carbamate (1.14 g) in a tetrahydrofuran solution (10.3 mL) of lithium aluminum hydride (626 mg) under ice-cooling. ) In tetrahydrofuran (10.3 mL) was added, and the mixture was stirred under ice-cooling for 4 hours. Water (0.626 mL), a 15% aqueous sodium hydroxide solution (0.626 mL), and water (1.88 mL) were added to the reaction mixture, and the mixture was stirred for 2 hours. The obtained suspension was filtered through Celite, and the filtrate was concentrated to obtain tert-butyl N- [2- [4- (aminomethyl) phenyl] ethyl] carbamate (915 mg).
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.43 (9H, s), 2.78 (2H, t, J = 6.7 Hz), 3.36 (2H, q, J = 6.7 Hz), 3.84 (2H, s) , 4.50-4.70 (1H, m), 7.16 (2H, d, J = 7.9 Hz), 7.25 (2H, d, J = 7.9 Hz).
HRMS (ESI ⁺ ): 251.17565 [M + H] ⁺

Dichloromethane solution of tert-butyl N-[[6- (hydroxymethyl) pyridine-2-yl] methyl] -N-[(2-methylpropan-2-yl) oxycarbonyl] carbamate (200 mg) under an argon atmosphere. Triphenylphosphine (186 mg) and carbon tetrabromide (274 mg) were added to (2.96 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 1 hour. After concentrating the reaction solution under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) and tert-butyl N-[[6- (bromomethyl) pyridin-2-yl] methyl]. -N-[(2-Methylpropan-2-yl) oxycarbonyl] carbamate (222 mg) was obtained.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.45 (18H, s), 4.51 (2H, s), 4.91 (2H, s), 7.09 (1H, d, J = 7.9 Hz), 7.31 (1H, 1H, d, J = 7.9 Hz), 7.65 (1H, t, J = 7.9 Hz).
HRMS (ESI ⁺ ): 401.10834 [M + H] ⁺

N, N of tert-butyl N-[[6- (bromomethyl) pyridin-2-yl] methyl] -N-[(2-methylpropan-2-yl) oxycarbonyl] carbamate (220 mg) under an argon atmosphere -Dimethylamine (0.820 mL, 2 mol / L tetrahydrofuran solution) and potassium carbonate (227 mg) were added to a dimethylformamide solution (2.74 mL), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the insoluble matter was removed by filtration. After distilling off the solvent, the residue was purified by aminoated silica gel column chromatography (ethyl acetate / hexane = 33%) and tert-butyl N-[[6-[(dimethylamino) methyl] pyridine-2-yl] methyl]. -N-[(2-Methylpropan-2-yl) oxycarbonyl] carbamate (177 mg) was obtained.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.43 (18H, s), 2.28 (6H, s), 3.56 (2H, s), 4.92 (2H, s), 7.03 (1H, d, J = 7.9) Hz), 7.25 (1H, d, J = 7.9 Hz), 7.61 (1H, t, J = 7.9 Hz).
HRMS (ESI ⁺ ): 366.23889 [M + H] ⁺

Using the corresponding starting material and reactant, the following Reference Example 15-2 was obtained by the same method as in Reference Example 15-1, the method described in Step 18-2, or a method similar thereto.

Triethylamine (0.379 mL) and diphenylphosphate in a solution of 4-ethyl-6-methylpyridine-3-carboxylic acid (224 mg) in 1,4-dioxane (13.0 mL) at room temperature under an argon atmosphere. Azide (0.585 mL) was added, and the mixture was stirred at 60 ° C. for 1 hour and at 80 ° C. for 30 minutes. 1 mol / L hydrochloric acid (5.00 mL) was added to the reaction mixture, and the mixture was stirred at the same temperature for 15 minutes. Diisopropylamine (1 mL) was added to the reaction mixture, and purification was performed by aminoated silica gel column chromatography (hexane: ethyl acetate = 5: 1 to 0: 1) to 4-ethyl-6-methylpyridine-3-amine. (100 mg) was obtained.
^{1 1} H-NMR (DMSO-D ₆ , 400 MHz) δ: 1.25 (3H, t, J = 7.3 Hz), 2.43 (3H, s), 2.48 (2H, q, J = 7.3 Hz), 3.48 (2H, brs) ), 6.85 (1H, s), 7.16 (1H, s).
MS (EI ⁺ ): 136.1 [M] ⁺

Under an argon atmosphere, dimethylamine (1.55 mL, 2 mol / L tetrahydrofuran solution) and acetic acid (0.589 mL) were added to a tetrahydrofuran solution (10.3 mL) of 1H-indole-4-carbaldehyde (300 mg). In addition, after stirring at room temperature for 1 hour, sodium borohydride (875 mg) was added, and the mixture was stirred at room temperature for 4 hours. Saturated sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the insoluble matter was removed by filtration. After distilling off the solvent, the residue was purified by aminoated silica gel column chromatography (hexane: ethyl acetate = 2: 1) and 1- (1H-indole-4-yl) -N, N-dimethylmethaneamine (334 mg). Got
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 2.30 (6H, s), 3.71 (2H, s), 6.69 (1H, t, J = 2.4 Hz), 7.07 (1H, d, J = 7.3 Hz) , 7.16 (1H, t, J = 7.3 Hz), 7.21 (1H, t, J = 2.4 Hz), 7.31 (1H, d, J = 7.3 Hz), 8.22 (1H, brs).
HRMS (ESI ⁺ ): 175.12376 [M + H] ⁺

Triethylsilane (0.240 mL) in a trifluoroacetic acid solution (0.752 mL) of 1- (1H-indole-4-yl) -N, N-dimethylmethaneamine (131 mg) under an argon atmosphere under ice cooling. ) Was added, and the mixture was stirred under ice-cooling for 2 hours. Saturated sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the insoluble matter was removed by filtration. After distilling off the solvent, the residue was purified by aminoated silica gel column chromatography (hexane: ethyl acetate = 2: 1) and 1- (2,3-dihydro-1H-indole-4-yl) -N, N-dimethyl. Methanamine (103 mg) was obtained.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 2.29 (6H, s), 3.04 (2H, t, J = 8.3 Hz), 3.40 (2H, s), 3.56 (2H, t, J = 8.3 Hz) , 6.57 (1H, d, J = 7.9 Hz), 6.68 (1H, d, J = 7.9 Hz), 7.00 (1H, t, J = 7.9 Hz).
HRMS (EI ⁺ ): 176.13135 [M] ⁺

In an argon atmosphere, 4-methyl-6-nitro-1,3-benzothiazole-2-amine (1.00 g) in a mixed solution of dichloromethane (25.0 mL) and tetrahydrofuran (25.0 mL) at room temperature. Di-tert-butyl dicarbonate (1.15 g) and N, N-dimethyl-4-aminopyridine were added and stirred for 20 hours. After removing the insoluble matter of the reaction solution by filtration, the solvent and the like are distilled off under reduced pressure, and the residue is purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 to 1: 1) to obtain tert-butyl N-. (4-Methyl-6-nitro-1,3-benzothiazole-2-yl) carbamate (1.30 g) was obtained.
^{1 1} H-NMR (DMSO-D ₆ , 400MHz) δ: 1.51 (9H, s), 2.60 (3H, s), 8.10 (1H, dd, J = 2.4, 1.2 Hz), 8.81 (1H, d, J = 2.4 Hz), 12.27 (1H, s).
MS (ESI-): 308.1 [MH] ^-

It was synthesized in the same manner as in Reference Example 5 using tert-butyl N- (4-methyl-6-nitro-1,3-benzothiazole-2-yl) carbamate.
^{1 1} H-NMR (DMSO-D ₆ , 400MHz) δ: 1.47 (9H, s), 2.38 (3H, s), 4.97 (2H, s), 6.48 (1H, d, J = 2.4 Hz), 6.78 (1H) , d, J = 2.4 Hz), 11.37 (1H, s).
MS (ESI ⁺ ): 280.1 [M + H] ⁺

N, N-diisopropylethylamine (0.340 mL) and 1- (in an argon atmosphere, in a solution of tert-butyl N-piperidine-4-ylcarbamate (200 mg) in tetrahydrofuran (5.00 mL) at room temperature. 3-Bromopropyl) pyrrolidine hydrobromide (300 mg) was added, and the mixture was stirred at 40 ° C. for 24 hours. The reaction mixture was added to water, and the mixture was extracted 3 times with ethyl acetate. The combined extraction layers were dried over anhydrous sodium sulfate, and the insoluble material was removed by filtration. After distilling off the solvent under reduced pressure, the residue is roughly purified by aminoated silica gel column chromatography (ethyl acetate: methanol = 1: 0 to 9: 1) to obtain tert-butyl N- [1- (3- (3- (3-)) containing impurities. Pyrrolidine-1-ylpropyl) piperidine-4-yl] carbamate (169 mg) was obtained. The obtained crude product was used as it was in Reference Example 22 without further purification.

In a solution of tert-butyl N- [1- (3-pyrrolidine-1-ylpropyl) piperidine-4-yl] carbamate (163 mg) containing the impurities obtained in Reference Example 21 in dichloromethane (1.00 mL). , Trifluoroacetic acid (1.00 mL) was added at room temperature, and the mixture was stirred for 10 minutes. After distilling off the solvent of the reaction solution under reduced pressure, the residue was used as it was in Example 1-56 as a trifluoroacetate salt of 1- (3-pyrrolidine-1-ylpropyl) piperidine-4-amine.

Under an argon atmosphere, 55% sodium hydride (55.4 mg) in a solution of N, N-dimethylformamide (2.00 mL) at 0 ° C. (5-bromopyridine-2-yl) methanol (200 mg). N, N-dimethylformamide (1.00 mL) solution was added dropwise and stirred for 15 minutes, then a solution of methyl iodide (72.8 μL) in N, N-dimethylformamide (1.00 mL) was added dropwise to room temperature. Was stirred for 1 hour. The reaction mixture was added to saturated brine, and the mixture was extracted twice with ethyl acetate. The combined extraction layers are washed in the order of water and saturated brine, dried over anhydrous sodium sulfate, the insoluble material is filtered off, and the solvent and the like are distilled off under reduced pressure to obtain 5-bromo-2- (methoxymethyl) pyridine. : N, N-dimethylformamide = 1: 0.45 mixture (227 mg) was obtained.
^{1 1} H-NMR (CDCl ₃ , 400MHz) δ: 3.48 (3H, s), 4.54 (2H, s), 7.34 (1H, d, J = 8.5 Hz), 7.82 (1H, dd, J = 8.5, 2.4 Hz) ), 8.62 (1H, d, J = 2.4 Hz).

Under an argon atmosphere, 5-bromo-2- (methoxymethyl) pyridine (210 mg), benzophenone imine (0.210 mL), tripotassium phosphate (552 mg), tris (dibenzylideneacetone) dipalladium (0) chloroform 1,2-Dimethoxyethane (2.00 mL) solution of complex (26.9 mg) and 2-di-tert-butylphosphino-2', 4', 6'-triisopropylbiphenyl (26.5 mg) Was stirred at 40 ° C. for 4 hours. After removing the insoluble matter by filtration using Celite, 1 mol / L hydrochloric acid was added to the reaction solution to adjust the pH to 1, and the mixture was stirred at room temperature for 10 minutes. After washing the reaction solution with ethyl acetate, a saturated aqueous sodium hydrogen carbonate solution was added to the aqueous layer to adjust the pH to 8. The reaction mixture was purified by aminoated silica gel column chromatography (hexane: ethyl acetate = 3: 1 to 0: 1) to obtain 6- (methoxymethyl) pyridine-3-amine (66.0 mg).
^{1 1} H-NMR (CDCl ₃ , 400MHz) δ: 3.43 (3H, s), 3.69 (2H, brs), 4.46 (2H, s), 6.99 (1H, dd, J = 8.5, 2.4 Hz), 7.18 (1H) , d, J = 8.5 Hz), 8.06 (1H, d, J = 2.4 Hz).
MS (EI ⁺ ): 138.1 [M] ⁺

tert-Butyl- (4-cyanobenzyl) (methyl) carbamate (626 mg), 10% palladium carbon (130 mg) and methanol (20 mL) were stirred under a hydrogen atmosphere for 5 days. The reaction was filtered and the filtrate was concentrated under reduced pressure to give tert-butyl (4- (aminomethyl) benzyl) (methyl) carbamate (597 mg). The crude product was not purified and was used in the next reaction.
^{1 1} H-NMR (270 MHz, CDCl ₃ ) δ: 1.48 (9H, s), 1.68 (2H, s), 2.81 (3H, s), 4.41 (2H, s), 7.09-7.34 (4H, m).
MS (ESI ⁺ ): 251.28 [M + H] ⁺

A mixture of tert-butyl (4- (aminomethyl) benzyl) (methyl) carbamate (597 mg), paraformaldehyde (573 mg) and trifluoroethanol (20 mL) was stirred at room temperature for 15 minutes and sodium boron hydride (597 mg). 361 mg) was added and the mixture was stirred overnight at room temperature. The solvent was concentrated under reduced pressure, water was added, and the mixture was extracted twice with ethyl acetate. The mixture was concentrated under reduced pressure and purified by aminopropyl silica gel chromatography to obtain tert-butyl (4-((dimethylamino) methyl) benzyl) (methyl) carbamate (424 mg).
^{1 1} H-NMR (270 MHz, CDCl ₃ ) δ: 1.48 (9H, s), 2.23 (6H, s), 2.81 (3H, br s), 3.40 (2H, s), 4.40 (2H, s), 7.17 (2H, d, J = 8.1 Hz), 7.26 (2H, d, J = 8.1 Hz).
MS (ESI ⁺ ): 278.20 [M + H] ⁺

tert-Butyl (4-((dimethylamino) methyl) benzyl) (methyl) carbamate (424 mg) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added thereto, and the mixture was stirred overnight. Add 2N aqueous sodium hydroxide solution, adjust pH to 13 to 14, extract twice with dichloromethane, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and concentrate N, N-dimethyl-1- (4-((methylamino) methyl) phenyl). Methylamine (244 mg) was obtained.
^{1 1} H-NMR (270 MHz, CDCl ₃ ) δ: 2.23 (s, 6H), 2.45 (s, 3H), 3.40 (s, 2H), 3.73 (s, 2H), 7.26 (s, 4H).
MS (ESI ⁺ ): 179.18 [M + H] ⁺

Sodium nitrite (654 mg) in acetic acid (1.2 mL) solution of ethyl 4-methyl-3-oxopentanoate (1.5 g) cooled to 10 ° C so that the temperature of the solution is 20 ° C or lower. (1.2 mL) was added dropwise. After completion of the dropping, the reaction solution was returned to room temperature and stirred for 1 hour. Then, the reaction solution was extracted 3 times with diethyl ether. The combined organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give ethyl 2- (hydroxyimino) -4-methyl-3-oxopentanoate (1.85 g). The crude product was subjected to the next reaction without purification.
MS (ESI ⁺ ): 188.10 [M + H] ⁺

A solution of sodium acetate trihydrate (811 mg) and 5,5-dimethyl-1,3-cyclohexadione (1.39 g) in acetic acid (40 mL) was heated and stirred at 70 ° C. While controlling the reaction temperature to 70-80 ° C., a solution of ethyl 2- (hydroxyimino) -4-methyl-3-oxopentanoate (1.85 g) in acetic acid (20 mL) was added dropwise, and at the same time, zinc powder was added. (1.03 g) was added over 30 minutes. The reaction solution was heated to 100 ° C. and stirred for 1 hour, then cooled to 70 ° C., water was added, and the reaction solution was heated to 100 ° C. again and stirred for 6 hours. The reaction solution was returned to room temperature, added to an ice-water mixed solution, and extracted with dichloromethane. The combined organic layer was washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purified by silica gel column chromatography (chloroform / methanol), ethyl 3-isopropyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate (986 mg) Got
^{1 1} H-NMR (270 MHz, CDCl ₃ ) δ: 1.10 (6H, s), 1.32 (6H, d, J = 6.9 Hz), 1.38 (3H, t, J = 7.3 Hz), 2.37 (2H, s) , 2.66 (2H, s), 4.07 (1H, m), 4.35 (2H, q, J = 7.3 Hz), 8.95 (1H, brs).
MS (ESI ⁺ ): 278.23 [M + H] ⁺

Ethyl 3-isopropyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate (980 mg), potassium hydroxide (496 mg) in ethanol (10 mL) ) And water (3 mL) were heated and stirred under reflux conditions for 6 hours. The reaction mixture was cooled to 60 ° C., neutralized with acetic acid, and water was added. The precipitated solid is filtered, washed with water, and dried to dry 3-isopropyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid (570 mg). ) Was obtained.
^{1 1} H-NMR (500 MHz, CDCl ₃ + CD ₃ OD) δ: 1.10 (6H, s), 1.31 (6H, d, J = 7.0 Hz), 2.36 (2H, s), 2.66 (2H, s), 3.42 (1H, m), 4.06 (1H, m, J = 7.0 Hz).
MS (ESI ⁺ ): 250.19 [M + H] ⁺

Using the corresponding starting material and reactant, the same method as in Reference Example 30-1, the method described in Steps 26-1 to 26-2 and 25-1, or a method similar thereto, or the method described in the literature. Alternatively, 30-6 was obtained from the following Reference Examples 30-2 by a method similar thereto.

Ethyl 3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate in a solution of sodium borohydride (115 mg) in tetrahydrofuran (10 mL) (200 mg) was added and the mixture was cooled to −5 ° C. Boron trifluoride diethyl ether complex (0.54 mL) was slowly added under a nitrogen stream, and after dropping, the cooling bath was removed, the temperature was returned to room temperature, and the mixture was stirred for 2 hours. The reaction mixture was added to ice water, and the precipitated solid was collected by filtration. The mixture was washed with water and dried under reduced pressure to give ethyl 3-ethyl-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-2-carboxylate (193 mg).
¹ H-NMR (270 MHz, CDCl ₃ ) δ: 0.95 (6H, s), 1.10 (3H, t, J = 7.5 Hz), 1.31 (3H, t, J = 7.0 Hz), 1.52 (2H, t, J = 6.5 Hz), 2.34 (2H, s), 2.43 (2H, t, J = 6.5 Hz), 2.72 (2H, q, J = 7.5 Hz), 4.29 (2H, q, J = 7.0 Hz), 8.45 (1H, brs).
MS (ESI ⁺ ): 250.33 [M + H] ⁺

Add 1N potassium hydroxide (5 mL) to an ethanol solution (4 mL) of ethyl 3-ethyl-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-2-carboxylate (182 mg). , 70 ° C. for 12 hours. The reaction mixture was neutralized with a 1N aqueous hydrochloric acid solution and extracted twice with chloroform. After drying over magnesium sulfate, the mixture was filtered and concentrated under reduced pressure to give 3-ethyl-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid (115 mg).
MS (ESI ⁺ ): 222.26 [M + H] ⁺

Methyl 4-bromo-2-methylbenzoate (500 mg), rac-2,2'-bis (diphenylphosphino) in a toluene solution (18.2 mL) of pyridine-4-amine (171 mg) under an argon atmosphere. ) -1,1'-binaphthyl (22.7 mg), palladium (II) acetate (8.2 mg) and cesium carbonate (2.96 g) were added, and the mixture was stirred at 120 ° C. for 8 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the insoluble matter was removed by filtration. After distilling off the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1-ethyl acetate: methanol = 5: 1) and methyl 2-methyl-4- (pyridine-4-ylamino) benzoate. (79.0 mg) was obtained.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 2.61 (3H, s), 3.88 (3H, d, J = 1.2 Hz), 6.26 (1H, brs), 6.94 (2H, dd, J = 6.1, 1.2) Hz), 7.01 (1H, s), 7.02-7.05 (1H, m), 7.95 (1H, d, J = 8.5 Hz), 8.38 (2H, d, J = 6.1 Hz).
HRMS (FI ⁺ ): 242.10567 [M] ⁺

Using the corresponding starting materials and reactants, the following Reference Examples 33-2 to 33-14 were obtained by the same method as in Reference Example 33-1, the method described in Step 27-1, or a method similar thereto. ..

Lithium hydroxide in a mixed solution of methyl 2-methyl-4- (pyridin-4-ylamino) benzoate (79.0 mg) in methanol- tetrahydrofuran-water (1.63 mL, 1: 1: 1) under an argon atmosphere. Monohydrate (20.5 mg) was added and the mixture was stirred at room temperature for 18 hours. After concentrating the reaction solution under reduced pressure, 1 mol / L hydrochloric acid was added to adjust the pH to 5, and the resulting solid was collected by filtration to obtain 2-methyl-4- (pyridine-4-ylamino) benzoic acid (60. 6 mg) was obtained.
¹ H-NMR (DMSO-D ₆ , 400MHz) δ: 2.52 (3H, s), 7.03 (2H, d, J = 6.1 Hz), 7.05 (1H, d, J = 1.8 Hz), 7.08 (1H, dd) , J = 8.5, 1.8 Hz), 7.84 (1H, d, J = 8.5 Hz), 8.27 (2H, d, J = 6.1 Hz), 9.10 (1H, s), 12.44 (1H, brs).
HRMS (ESI ⁺ ): 229.09846 [M + H] ⁺

Using the corresponding starting materials and reactants, the following Reference Examples 34-2 to 34-14 were obtained by the same method as in Reference Example 34-1 and the method described in Step 25-1 or a method similar thereto. ..

In an argon atmosphere, in a solution of N, N-dimethylethane-1,2-diamine (1.31 mL) and ethyl 4-fluorobenzoate (0.877 mL) in dimethylsulfoxide (10.0 mL) at room temperature. Potassium carbonate (1.66 g) was added, and the mixture was stirred at 80 ° C. for 25.5 hours. The reaction mixture was added to water, and the mixture was extracted 3 times with ethyl acetate. The combined extraction layers were washed in the order of water and saturated brine, dried over anhydrous sodium sulfate, and the insoluble material was removed by filtration. After distilling off the solvent under reduced pressure, the residue was purified by amination silica gel column chromatography (hexane: ethyl acetate = 9: 1 to 0: 1) to carry out ethyl 4- [2- (dimethylamino) ethylamino] benzoate. (510 mg) was obtained.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.36 (3H, t, J = 7.3 Hz), 2.25 (6H, s), 2.53-2.59 (2H, m), 3.15-3.21 (2H, m), 4.31 (2H, q, J = 7.3 Hz), 4.71-4.83 (1H, br s), 6.56 (2H, d, J = 8.6 Hz), 7.87 (2H, d, J = 8.6 Hz).

Ethyl 4- [2- (dimethylamino) ethylamino] benzoate (35.4 mg) in ethanol (0.250 mL) and water (0.250 mL) in a mixed solution at room temperature with lithium hydroxide ( 4.30 mg) was added and stirred for 15 hours, at 50 ° C. for 2.5 hours, and at 70 ° C. for 5 hours, and then 1 mol / L hydrochloric acid was added to the reaction solution to adjust the pH to 1. After distilling off the solvent of the reaction solution under reduced pressure, the residue was used as it was in Example 6-66 as a hydrochloride of 4- [2- (dimethylamino) ethylamino] benzoic acid.

2-Chloro-N, N-dimethylethane in a solution of ethyl 4-hydroxybenzoate (332 mg) and potassium carbonate (967 mg) in N, N-dimethylformamide (4.00 mL) at room temperature under an argon atmosphere. Amine hydrochloride (317 mg) was added, and the mixture was stirred at 110 ° C. for 29 hours. The reaction mixture was added to water, and the mixture was extracted twice with ethyl acetate. The combined extraction layers were washed in the order of water and saturated brine, dried over anhydrous sodium sulfate, and the insoluble material was removed by filtration. After distilling off the solvent under reduced pressure, the residue was purified by aminoated silica gel column chromatography (hexane: ethyl acetate = 9: 1 to 1: 2) to carry out ethyl 4- [2- (dimethylamino) ethoxy] benzoate (. 398 mg) was obtained.
¹ H-NMR (CDCl ₃ , 400MHz) δ: 1.38 (3H, t, J = 7.3 Hz), 2.34 (6H, s), 2.75 (2H, t, J = 5.5 Hz), 4.11 (2H, t, J) = 5.5 Hz), 4.34 (2H, q, J = 7.3 Hz), 6.93 (2H, d, J = 8.6 Hz), 7.99 (2H, d, J = 8.6 Hz).

Ethyl 4- [2- (dimethylamino) ethoxy] benzoate was used for synthesis in the same manner as in Reference Example 36, and the crude product was used in the next step without purification.

Acetic acid (0.755 mL) in a solution of 1-methylpiperidine-4-one (1.00 g) and methyl 4-aminobenzoate (0.917 mL) in dichloromethane (30.0 mL) at room temperature under an argon atmosphere. ) Was added, and the mixture was stirred for 15 minutes, then sodium triacetoxyborohydride (4.22 g) was added to the reaction solution, and the mixture was stirred for 25 hours. The reaction mixture was added to saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted twice with ethyl acetate. The combined extraction layers were washed in the order of water and saturated brine, dried over anhydrous sodium sulfate, and the insoluble material was removed by filtration. After distilling off the solvent under reduced pressure, the residue was purified by amination silica gel column chromatography (ethyl acetate) to obtain methyl 4-[(1-methylpiperidin-4-yl) amino] benzoate (705 mg). ..
^{1 1} H-NMR (DMSO-D ₆ , 400MHz) δ: 1.32-1.46 (2H, m), 1.79-1.89 (2H, m), 1.93-2.04 (2H, m), 2.15 (3H, s), 2.65- 2.76 (2H, m), 3.15-3.29 (1H, m), 3.72 (3H, s), 6.38 (1H, d, J = 7.3 Hz), 6.57 (2H, d, J = 9.1 Hz), 7.65 (2H) , d, J = 9.1 Hz).
MS (FI ⁺ ): 248.2 [M] ⁺

Lithium hydroxide at room temperature in a mixed solution of methyl 4-[(1-methylpiperidin-4-yl) amino] benzoate (705 mg) in methanol (7.50 mL) and water (7.50 mL). (68.0 mg) was added, and the mixture was stirred for 18 hours, at 40 ° C. for 7 hours, and at 60 ° C. for 2.5 hours. After washing the reaction solution with ethyl acetate, 1 mol / L hydrochloric acid was added to the aqueous layer to adjust the pH to 1. After distilling off the solvent of the reaction solution under reduced pressure, the residue was used as it was in Example 6-59 as a hydrochloride of 4-[(1-methylpiperidin-4-yl) amino] benzoic acid.

Under an argon atmosphere, a solution of methyl 4-bromo-2-methylbenzoate (300 mg) in 1,2-dimethoxyethane (6.55 mL), pyridine-4-ylboronic acid (241 mg), and bis (triphenylphosphine) Palladium (II) dichloride (91.9 mg) and a 2 mol / L aqueous sodium carbonate solution (1.97 mL) were added, and the mixture was stirred at 60 ° C. for 8 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the insoluble matter was removed by filtration. After distilling off the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2) to obtain methyl 2-methyl-4-pyridin-4-ylbenzoate (215 mg).
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 2.69 (3H, s), 3.93 (3H, s), 7.49-7.53 (4H, m), 8.03 (1H, d, J = 8.5 Hz), 8.69 ( 2H, d, J = 6.1 Hz).
HRMS (ESI ⁺ ): 228.10273 [M + H] ⁺

Lithium hydroxide monohydrate in a mixed solution of methyl 2-methyl-4-pyridin-4-ylbenzoate (215 mg) in methanol- tetrahydrofuran-water (4.74 mL, 1: 1: 1) under an argon atmosphere. (59.6 mg) was added, and the mixture was stirred at room temperature for 7 hours. After concentrating the reaction solution under reduced pressure, 1 mol / L hydrochloric acid was added to adjust the pH to 5, the resulting solid was collected by filtration, and 2-methyl-4-pyridin-4-ylbenzoic acid (164 mg) was added. Obtained.
¹ H-NMR (DMSO-D ₆ , 400MHz) δ: 2.62 (3H, s), 7.72 (1H, dd, J = 7.9, 1.8 Hz), 7.75-7.78 (3H, m), 7.95 (1H, d, J = 7.9 Hz), 8.67 (2H, d, J = 6.1 Hz), 12.98 (1H, brs).
HRMS (ESI ⁺ ): 214.08724 [M + H] ⁺

Potassium carbonate (929 mg) and tetrakis (triphenylphosphine) palladium (0) in a solution of ethyl 4-bromobenzoate (0.718 mL) in 1,4-dioxane (15.0 mL) at room temperature under an argon atmosphere. ) (518 mg), and 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,6-dihydro-2H-pyridine (1. 00 g) was added, and the mixture was stirred at 110 ° C. for 22 hours. The reaction mixture was added to water, and the mixture was extracted twice with ethyl acetate. The combined extraction layers were washed in the order of water and saturated brine, dried over anhydrous sodium sulfate, and the insoluble material was removed by filtration. After distilling off the solvent under reduced pressure, the residue was purified by aminoated silica gel column chromatography (hexane: ethyl acetate = 9: 1 to 1: 2) to carry out ethyl 4- (1-methyl-3,6-dihydro-2H). -Pyridine-4-yl) benzoate (1.16 g) was obtained.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.39 (3H, t, J = 6.7 Hz), 2.42 (3H, s), 2.56-2.64 (2H, m), 2.65-2.71 (2H, m), 3.12 -3.16 (2H, m), 4.37 (2H, q, J = 6.7 Hz), 6.17-6.22 (1H, m), 7.44 (2H, d, J = 8.6 Hz), 7.99 (2H, d, J = 8.6 Hz) Hz).

Using the corresponding starting materials and reactants, the following Reference Example 43-2 was obtained by the same method as in Reference Example 43-1, the method described in Step 31-1 or a method similar thereto.

Under an argon atmosphere, 10% palladium carbon in an ethanol (6.00 mL) solution of ethyl 4- (1-methyl-3,6-dihydro-2H-pyridin-4-yl) benzoate (300 mg) at room temperature. (60.0 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 4 hours, and then hydrogen in the reaction vessel was replaced with argon. After filtering the reaction solution with Celite, the residue obtained by distilling off the solvent of the filtrate under reduced pressure is purified by aminoated silica gel column chromatography (hexane: ethyl acetate = 5: 1 to 0: 1) to obtain ethyl. 4- (1-Methylpiperidin-4-yl) benzoate (295 mg) was obtained.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.38 (3H, t, J = 7.3 Hz), 1.75-1.88 (4H, m), 2.00-2.10 (2H, m), 2.33 (3H, s), 2.47 -2.59 (1H, m), 2.94-3.02 (2H, m), 4.36 (2H, q, J = 7.3 Hz), 7.29 (2H, d, J = 8.6 Hz), 7.98 (2H, d, J = 8.6 Hz) Hz).

Using the corresponding starting material and reactant, the following Reference Example 44-2 was obtained by the same method as in Reference Example 44-1, the method described in Step 31-2, or a method similar thereto.

Lithium hydroxide in a mixed solution of tert-butyl 4- (4-ethoxycarbonylphenyl) piperidin-1-carboxylate (140 mg) in ethanol (1.00 mL) and water (1.00 mL) at room temperature. (15.1 mg) was added and the mixture was stirred for 22 hours. After adjusting the pH to 3 by adding 1 mol / L hydrochloric acid to the reaction mixture, the mixture was extracted twice with ethyl acetate. The combined extraction layers were washed in the order of water and saturated brine, dried over anhydrous sodium sulfate, and the insoluble material was removed by filtration. After distilling off the solvent under reduced pressure, the residue was washed with diisopropyl ether to give 4- [1-[(2-methylpropan-2-yl) oxycarbonyl] piperidine-4-yl] benzoic acid (97.0 mg). Got
^{1 1} H-NMR (DMSO-D ₆ , 400MHz) δ: 1.40 (9H, s), 1.42-1.57 (2H, m), 1.69-1.81 (2H, m), 2.69-2.93 (3H, m), 3.96- 4.17 (2H, m), 7.36 (2H, d, J = 8.6 Hz), 7.86 (2H, d, J = 8.6 Hz), 12.80 (1H, br s).

Lithium hydroxide (37.1 mg) of ethyl 4- (1-methylpiperidin-4-yl) benzoate (37.1 mg) in a mixed solution of ethanol (0.250 mL) and water (0.250 mL) at room temperature After adding 4.31 mg) and stirring for 18 hours, 1 mol / L hydrochloric acid was added to the reaction solution to adjust the pH to 1. After distilling off the solvent of the reaction solution under reduced pressure, the residue was used as it was in Example 6-69 as a hydrochloride of 4- (1-methylpiperidin-4-yl) benzoic acid.

A mixed solution of ethyl 4- (1-methyl-3,6-dihydro-2H-pyridin-4-yl) benzoate (36.8 mg) in ethanol (0.250 mL) and water (0.250 mL). Lithium hydroxide (4.31 mg) was added to the mixture at room temperature, and the mixture was stirred for 44 hours and at 70 ° C. for 20 hours, and then 1 mol / L hydrochloric acid was added to the reaction solution to adjust the pH to 1. After distilling off the solvent of the reaction solution under reduced pressure, the residue was used as it was in Example 6-68 as a hydrochloride of 4- (1-methyl-3,6-dihydro-2H-pyridin-4-yl) benzoic acid.

Under an argon atmosphere, methyl 4-chloro-6-methylpyridine-3-carboxylate (700 mg), potassium vinyl trifluoroborate (556 mg) and cesium carbonate (3.68 g) in tetrahydrofuran (15.0 mL)-. [1,1'-Bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (154 mg) was added to a mixed solution of water (3.00 mL) at room temperature, and the mixture was stirred under heating and reflux for 14.5 hours. did. The insoluble matter of the reaction solution was removed by filtration with Celite, water was added, and the mixture was extracted twice with ethyl acetate. The combined extraction layers were washed in the order of water and saturated brine, dried over anhydrous sodium sulfate, and the insoluble material was removed by filtration. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 0 to 3: 1) to carry out methyl 4-ethenyl-6-methylpyridine-3-carboxylate (345 mg). ) Was obtained.
^{1 1} H-NMR (CDCl ₃ , 400MHz) δ: 2.61 (3H, s), 3.92 (3H, s), 5.53 (1H, dd, J = 10.9, 1.2 Hz), 5.83 (1H, dd, J = 17.6, 1.2 Hz), 7.32 (1H, s), 7.51 (1H, dd, J = 17.6, 10.9), 8.99 (1H, s).
MS (ESI ⁺ ): 178.1 [M + H] ⁺

Under an argon atmosphere, 10% palladium carbon (34.5 mg) was added to a solution of methyl 4-ethenyl-6-methylpyridine-3-carboxylate (345 mg) in methanol (10.0 mL) at room temperature, and hydrogen was added. After stirring in an atmosphere for 1.5 hours, hydrogen in the reaction vessel was replaced with argon. After filtering the reaction solution with Celite, the solvent of the filtrate and the like were distilled off under reduced pressure to obtain methyl 4-ethyl-6-methylpyridine-3-carboxylate (349 mg).
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.24 (3H, t, J = 7.3 Hz), 2.58 (3H, s), 2.99 (2H, q, J = 7.3 Hz), 3.92 (3H, s), 7.07 (1H, s), 8.95 (1H, s).
MS (EI ⁺ ): 179.1 [M] ⁺

Lithium hydroxide monohydrate (At room temperature) in a mixed solution of methyl 4-ethyl-6-methylpyridine-3-carboxylate (349 mg) in methanol (5.00 mL) and water (5.00 mL). 123 mg) was added and the mixture was stirred for 18 hours. After adjusting the pH to 5 to 6 by adding 1 mol / L hydrochloric acid to the reaction solution, the solvent and the like were distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol = 4: 1) to obtain 4-ethyl-6-methylpyridine-3-carboxylic acid (322 mg).
¹ H-NMR (DMSO-D ₆ , 400MHz) δ: 1.17 (3H, t, J = 7.9 Hz), 2.49 (3H, s), 2.94 (2H, q, J = 7.9 Hz), 7.22 (1H, s) ), 8.79 (1H, s).
MS (ESI ⁺ ): 166.1 [M + H] ⁺

Heat a solution of ethyl 2-chloro-4,4,4-trifluoro-3-oxobutanoate (1.14 mL) and pyridine-3-carbothioamide (1.00 g) in ethanol (10.0 mL). The mixture was stirred under reflux for 26 hours. The reaction mixture was added to water, and the mixture was extracted twice with ethyl acetate. The combined extraction layers were washed in the order of water and saturated brine, dried over anhydrous sodium sulfate, and the insoluble material was removed by filtration. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 to 0: 1) and then washed with diisopropyl ether to carry out ethyl 4-hydroxy-2-pyridine-3. -Il-4- (trifluoromethyl) -5H-1,3-thiazole-5-carboxylate (677 mg) was obtained.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.33 (3H, t, J = 7.3 Hz), 4.31 (2H, q, J = 7.1 Hz), 4.90 (1H, s), 7.40-7.43 (1H, m) ), 8.00 (1H, dt, J = 8.1, 2.0 Hz), 8.67 (1H, dd, J = 4.8, 1.8 Hz), 8.86 (1H, s), 9.54 (1H, d, J = 3.0 Hz).
MS (FI ⁺ ): 320.1 [M] ⁺

Ethyl 4-hydroxy-2-pyridine-3-yl-4- (trifluoromethyl) -5H-1,3-thiazole-5-carboxylate (632 mg) in toluene (10.0 mL) at room temperature Paratoluenesulfonic acid monohydrate (1.12 g) was added, and the mixture was stirred under heating and reflux for 1 hour. The reaction mixture was added to saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted twice with ethyl acetate. The combined extraction layers were washed in the order of water and saturated brine, dried over anhydrous sodium sulfate, and the insoluble material was removed by filtration. After distilling off the solvent under reduced pressure, the residue was purified by aminoated silica gel column chromatography (ethyl acetate) to carry out ethyl 2-pyridine-3-yl-4- (trifluoromethyl) -1,3-thiazole-5. Carboxylate (155 mg) was obtained.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.42 (3H, t, J = 7.3 Hz), 4.44 (2H, q, J = 7.3 Hz), 7.45 (1H, dd, J = 7.3, 4.8 Hz), 8.32 (1H, td, J = 4.8, 2.8 Hz), 8.76 (1H, dd, J = 4.8, 1.8 Hz), 9.19 (1H, d, J = 1.8 Hz).
MS (ESI ⁺ ): 303.0 [M + H] ⁺

Mixing of ethyl 2-pyridine-3-yl-4- (trifluoromethyl) -1,3-thiazole-5-carboxylate (150 mg) in ethanol (2.50 mL) and water (2.50 mL) Lithium hydroxide (17.8 mg) was added to the solution at room temperature, and the mixture was stirred for 30 minutes. The reaction mixture was washed with ethyl acetate, 1 mol / L hydrochloric acid was added to the aqueous layer to adjust the pH to 3, and the mixture was extracted twice with ethyl acetate. The combined extraction layers were washed in the order of water and saturated brine, dried over anhydrous sodium sulfate, and the insoluble material was removed by filtration. After distilling off the solvent under reduced pressure, the residue was washed with diisopropyl ether to obtain 2-pyridine-3-yl-4- (trifluoromethyl) -1,3-thiazole-5-carboxylic acid (95.0 mg). Obtained.
¹ H-NMR (DMSO-D ₆ , 400MHz) δ: 7.60 (1H, dt, J = 7.7, 3.2 Hz), 8.40 (1H, dt, J = 8.1, 2.0 Hz), 8.77 (1H, td, J = 5.3, 1.4 Hz), 9.19 (1H, d, J = 2.4 Hz).
MS (ESI ⁺ ): 275.0 [M + H] ⁺

Under an argon atmosphere, pyridine (1.12 mL) and paratoluenesulfonyl chloride (1.76 g) were added to a dichloromethane solution (9.25 mL) of 2-cyclobutylethanol (926 mg), and the mixture was stirred at room temperature for 26 hours. .. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1 mol / L hydrochloric acid and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and the insoluble matter was removed by filtration. After distilling off the solvent, the residue was purified by aminoated silica gel column chromatography (hexane: ethyl acetate = 9: 1) to obtain 2-cyclobutylethyl 4-methylbenzenesulfonate (1.94 g).
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.54-1.62 (2H, m), 1.73 (2H, q, J = 6.7 Hz), 1.76-1.87 (2H, m), 1.94-2.02 (2H, m) ), 2.25-2.38 (1H, m), 2.45 (3H, s), 3.95 (2H, t, J = 6.7 Hz), 7.34 (2H, d, J = 8.5 Hz), 7.78 (2H, d, J = 8.5 Hz).
HRMS (FI ⁺ ): 254.09769 [M] ⁺

Under an argon atmosphere, tert-butoxypotassium in a solution of diethyl 2-[(2-methylpropan-2-yl) oxycarbonylamino] propanedioart (3.14 g) in N, N-dimethylformamide (19.1 mL). (1.20 g) was added, and the mixture was stirred at 70 ° C. for 30 minutes. After allowing the obtained reaction solution to cool to room temperature, an N, N-dimethylformamide solution (19.0 mL) of 2-cyclobutylethyl 4-methylbenzenesulfonate (1.94 g) was added, and the temperature was 70 ° C. The mixture was stirred for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the insoluble matter was removed by filtration. After distilling off the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) and diethyl 2- (2-cyclobutylethyl) -2-[(2-methylpropan-2-yl) oxy. Carbonylamino] propanedioart (1.76 g) was obtained.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.19-1.24 (2H, m), 1.25 (6H, t, J = 7.3 Hz), 1.43 (9H, s), 1.50-1.58 (2H, m), 1.74-1.87 (2H, m), 2.00-2.08 (2H, m), 2.12-2.20 (2H, m), 2.20-2.28 (1H, m), 4.18-4.28 (4H, m), 5.91 (1H, brs) ).
HRMS (ESI ⁺ ): 358.22297 [M + H] ⁺

Using the corresponding starting materials and reactants, the following Reference Examples 55-2 to 55-3 were obtained by the same method as in Reference Example 55-1, the method described in Step 34-2 or a method similar thereto. ..

Ethanol solution (24.6 mL) of diethyl 2- (2-cyclobutylethyl) -2-[(2-methylpropan-2-yl) oxycarbonylamino] propanedioate (1.76 g) under an argon atmosphere. A 2 mol / L potassium hydroxide aqueous solution (2.71 mL) was added thereto, and the mixture was stirred at room temperature for 4 hours. After concentrating the reaction mixture, 1 mol / L hydrochloric acid was added to adjust the pH to 2, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the insoluble matter was removed by filtration. After distilling off the solvent, 4-cyclobutyl-2-ethoxycarbonyl-2-[(2-methylpropan-2-yl) oxycarbonylamino] butanoic acid (1.64 g) was obtained.
^{1 1} H-NMR (DMSO-D ₆ , 400 MHz) δ: 1.14 (3H, t, J = 7.3 Hz), 1.19-1.24 (2H, m), 1.37 (9H, s), 1.43-1.52 (2H, m) , 1.71-1.84 (2H, m), 1.90-2.01 (4H, m), 2.12-2.22 (1H, m), 4.06-4.18 (2H, m), 6.38 (1H, brs).
HRMS (ESI ⁺ ): 330.19229 [M + H] ⁺

Using the corresponding starting materials and reactants, the following Reference Examples 56-2 to 56-3 were obtained by the same method as in Reference Example 56-1, the method described in Step 34-3, or a method similar thereto. ..

A solution of 4-cyclobutyl-2-ethoxycarbonyl-2-[(2-methylpropan-2-yl) oxycarbonylamino] butanoic acid (1.62 g) in 1,2-dichlorobenzene (9.84) under an argon atmosphere. mL) was stirred at 110 ° C. for 1 hour. After allowing the reaction solution to cool to room temperature, it was purified by silica gel column chromatography (hexane-hexane: ethyl acetate = 4: 1) and ethyl 4-cyclobutyl-2-[(2-methylpropan-2-yl) oxycarbonyl. Amino] Butanoart (1.27 g) was obtained.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 1.28 (3H, t, J = 7.3 Hz), 1.36-1.43 (2H, m), 1.45 (9H, s), 1.47-1.62 (4H, m), 1.65-1.74 (1H, m), 1.76-1.88 (2H, m), 1.99-2.07 (2H, m), 2.19-2.27 (1H, m), 4.14-4.26 (2H, m), 4.98 (1H, d) , J = 7.9 Hz).
HRMS (FI ⁺ ): 286.20177 [M] ⁺

Using the corresponding starting materials and reactants, the following Reference Examples 57-2 to 57-3 were obtained by the same method as in Reference Example 57-1, the method described in Step 34-4, or a method similar thereto. ..

Under an argon atmosphere, 2 mol / L potassium hydroxide in an ethanol solution (14.8 mL) of ethyl 4-cyclobutyl-2-[(2-methylpropan-2-yl) oxycarbonylamino] butanoate (1.27 g). An aqueous solution (3.34 mL) was added, and the mixture was stirred at room temperature for 16 hours. After concentrating the reaction solution, 1 mol / L hydrochloric acid was added to adjust the pH to 2, and the resulting solid was collected by filtration to obtain 4-cyclobutyl-2-[(2-methylpropan-2-yl) oxycarbonylamino]. Butanoic acid (1.02 g) was obtained.
^{1 1} H-NMR (DMSO-D ₆ , 400MHz) δ: 1.32-1.48 (2H, m), 1.38 (9H, s), 1.48-1.62 (4H, m), 1.72-1.84 (2H, m), 1.92- 2.02 (2H, m), 2.14-2.23 (1H, m), 3.79 (1H, td, J = 7.9, 4.8 Hz), 7.00 (1H, d, J = 7.9 Hz).
HRMS (FI ⁺ ): 258.16971 [M] ⁺

Using the corresponding starting materials and reactants, the following Reference Examples 58-2 to 58-3 were obtained by the same method as in Reference Example 58-1, the method described in Step 34-5, or a method similar thereto. ..

In a mixed solution of 4-cyclopropyl-2-[(2-methylpropane-2-yl) oxycarbonylamino] butanoic acid (200 mg) in methanol (4.00 mL) and toluene (4.00 mL), A 2.0 mol / L trimethylsilyldiazomethane-diethyl ether solution (0.615 mL) was added dropwise at room temperature, and the mixture was stirred for 20 minutes. Acetic acid was added to the reaction solution until foaming and disappearance of yellow coloring were confirmed, and then the residue obtained by distilling off the solvent under reduced pressure was added to methyl 4-cyclopropyl-2-[(2-methylpropan-2-yl) oxy. Carbonylamino] Butanoart was used as it was in Reference Example 60 and Reference Example 66.

Methyl 4-cyclopropyl-2-[(2-methylpropan-2-yl) oxycarbonylamino] obtained as a residue of Reference Example 59 under an argon atmosphere in a dichloromethane (4.00 mL) solution of butanoate at room temperature. Trifluoroacetic acid (4.00 mL) was added, and the mixture was stirred for 20 minutes. The residue obtained by distilling off the solvent of the reaction solution under reduced pressure was used as a trifluoroacetate salt of methyl 2-amino-4-cyclopropylbutanoate in Reference Example 65-6.

Under an argon atmosphere, n-butyllithium at −78 ° C. in a tetrahydrofuran solution (13.9 mL) of (2R) -3,6-dimethoxy-2-propane-2-yl-2,5-dihydropyrazine (766 mg). (2.55 mL, 1.63 mol / L, n-hexane solution) was added slowly, and the mixture was stirred at −78 ° C. for 15 minutes. Then, a tetrahydrofuran solution (6.94 mL) of 2-cyclopropylethyl 4-methylbenzenesulfonate (1.00 g) was slowly added, stirred at −78 ° C. for 1 hour, and then gradually heated to room temperature. The mixture was stirred for 16 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the insoluble matter was removed by filtration. After distilling off the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 30: 1) and (2S, 5R) -2- (2-cyclopropylethyl) -3,6-dimethoxy-5-propane. -2-Il-2,5-dihydropyrazine (555 mg) was obtained.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 0.00-0.04 (2H, m), 0.38 (1H, d, J = 1.8 Hz), 0.40 (1H, d, J = 1.8 Hz), 0.59-0.67 ( 1H, m), 0.69 (3H, d, J = 6.7 Hz), 1.05 (3H, d, J = 6.7 Hz), 1.08-1.26 (2H, m), 1.75-1.84 (1H, m), 1.88-1.97 (1H, m), 2.22-2.30 (1H, m), 3.67 (3H, s), 3.69 (3H, s), 3.92 (1H, dd, J = 3.6, 3.0 Hz), 4.04 (1H, td, J) = 6.7, 3.0 Hz).
HRMS (ESI ⁺ ): 253.19083 [M + H] ⁺

Under an argon atmosphere, a solution of (2S, 5R) -2- (2-cyclopropylethyl) -3,6-dimethoxy-5-propane-2-yl-2,5-dihydropyrazine (555 mg) in tetrahydrofuran (11. 0.5 mol / L hydrochloric acid (11.0 mL) was added to (0 mL), and the mixture was stirred at room temperature for 5 hours. A 25% aqueous ammonium solution was added to the reaction mixture to adjust the pH to 7, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the insoluble matter was removed by filtration. After concentrating the solvent under reduced pressure, methyl (2S) -2-amino-4-cyclopropylbutanoate was obtained. The obtained crude product was used as it was in Reference Example 63 without further purification.

Under an argon atmosphere, di-dicarbonate dicarbonate in an ethyl acetate-water mixed solution (11.0 mL, 1: 1) of a mixture of methyl (2S) -2-amino-4-cyclopropylbutanoate and impurities under ice cooling. -Tert-Butyl (1.06 g) and sodium carbonate (700 mg) were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the insoluble matter was removed by filtration. After distilling off the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) and methyl (2S) -4-cyclopropyl-2-[(2-methylpropan-2-yl) oxycarbonyl. Amino] butanoart (490 mg) was obtained.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 0.00-0.04 (2H, m), 0.40-0.45 (2H, m), 0.61-0.71 (1H, m), 1.21-1.29 (2H, m), 1.44 (9H, s), 1.67-1.77 (1H, m), 1.86-1.96 (1H, m), 3.74 (3H, s), 4.25-4.38 (1H, m), 4.90-5.10 (1H, m).
HRMS (ESI ⁺ ): 258.17006 [M + H] ⁺

Under an argon atmosphere, a mixed solution of methyl (2S) -4-cyclopropyl-2-[(2-methylpropan-2-yl) oxycarbonylamino] butanoate (490 mg) in methanol-tetrapropyl-water (9.52 mL,) Lithium hydroxide monohydrate (120 mg) was added to 3: 3: 1) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, pH was adjusted to 2 by adding 1 mol / L hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the insoluble matter was removed by filtration. After distilling off the solvent, (2S) -4-cyclopropyl-2-[(2-methylpropan-2-yl) oxycarbonylamino] butanoic acid (418 mg) was obtained.
^{1 1} H-NMR (DMSO-D ₆ , 400MHz) δ: 0.00-0.02 (2H, m), 0.32-0.41 (2H, m), 0.59-0.67 (1H, m), 1.18-1.26 (2H, m), 1.37 (9H, s), 1.58-1.68 (1H, m), 1.69-1.78 (1H, m), 3.85-3.92 (1H, m), 7.04 (1H, d, J = 7.9 Hz), 12.38 (1H, 1H, brs).
HRMS (ESI ⁺ ): 244.15499 [M + H] ⁺

Under an argon atmosphere, 3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxylic acid (200 mg) and methyl 2-amino-2-phenylacetate hydrochloride (182 mg) In a solution of N, N-dimethylformamide (4.50 mL) at room temperature, 1-hydroxybenzotriazole monohydrate (165 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride ( 191 mg) and N, N-diisopropylethylamine (0.616 mL) were added, and the mixture was stirred for 14 hours. The reaction solution was added to water, the resulting insoluble material was collected by filtration, and then washed with diisopropyl ether to obtain methyl 2-phenyl-2-[(3,6,6-trimethyl-4-oxo-5,7-dihydro). -1H-indole-2-carbonyl) amino] acetate (296 mg) was obtained.
^{1 1} H-NMR (DMSO-D ₆ , 400MHz) δ: 1.03 (3H, s), 1.04 (3H, s), 2.24 (2H, s), 2.49 (3H, s), 2.65 (2H, s), 3.68 (3H, s), 5.57 (1H, d, J = 6.7 Hz), 7.37-7.51 (5H, m), 8.20 (1H, d, J = 6.7 Hz), 11.71 (1H, s).
MS (ESI ⁺ ): 369.2 [M + H] ⁺

Using the corresponding starting materials and reactants, the following Reference Examples 65-2 to 65-6 were obtained by the same method as in Reference Example 65-1, the method described in Step 1-1, or a method similar thereto. ..

Under an argon atmosphere, a solution of methyl 4-cyclopropyl-2- [(2-methylpropan-2-yl) oxycarbonylamino] butanoate obtained as a residue of Reference Example 59 in dichloromethane (4.00 mL) at room temperature Trifluoroacetic acid (4.00 mL) was added and the mixture was stirred for 20 minutes. N, N-diisopropylethylamine (0.699 mL) and 2-phenylacetyl chloride (0.109 mL) were added to a dichloromethane (8.00 mL) solution of the residue obtained by distilling off the solvent of the reaction solution under reduced pressure at 0 ° C. Was added, and the mixture was stirred at room temperature for 30 minutes. Methyl 4-cyclopropyl-2-[(2-phenylacetyl) amino] butanoate (189 mg) was obtained by purifying the reaction solution by silica gel column chromatography (hexane: ethyl acetate = 9: 1 to 0: 1). Obtained.
^{1 1} H-NMR (CDCl ₃ , 400MHz) δ: -0.13--0.03 (2H, m), 0.32-0.40 (2H, m), 0.51-0.63 (1H, m), 1.01-1.17 (2H, m), 1.63-1.73 (1H, m), 1.83-1.95 (1H, m), 3.60 (2H, s), 3.70 (3H, s), 4.58-4.67 (1H, m), 5.85 (1H, d, J = 7.3) Hz), 7.26-7.41 (5H, m).
MS (ESI ⁺ ): 276.2 [M + H] ⁺

Methyl 2-[(3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carbonyl) amino] Hexanoate (1.22 g) in methanol (7.50 mL) , Lithium hydroxide monohydrate (220 mg) was added to a mixed solution of tetrahydrofuran (7.50 mL) and water (15.0 mL) at room temperature, and the mixture was stirred for 30 minutes. By adding 1 mol / L hydrochloric acid to the reaction solution and collecting the resulting insoluble matter by filtration, 2-[(3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-) Carbonyl) amino] caproic acid (1.09 g) was obtained.
HRMS (ESI ⁺ ): 335.19704 [M + H] ⁺

Using the corresponding starting materials and reactants, the following Reference Examples 67-2 to 67-7 were obtained by the same method as in Reference Example 67-1, the method described in Step 1-2, or a method similar thereto. ..

2-[(3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carbonyl) amino] hexanoic acid (250 mg) and 3- [4- (amino) under an argon atmosphere Methyl) Phenyl] Propan-1-ol (148 mg) in a solution of N, N-dimethylformamide (4.00 mL) at room temperature, 4- (4,6-dimethoxy-1,3,5-triazine-2. -Il) -4-methylmorpholinium chloride (248 mg) was added, and the mixture was stirred for 1 hour. The reaction mixture was added to water, and the mixture was extracted twice with ethyl acetate. The combined extraction layers were washed in the order of water and saturated brine, dried over anhydrous sodium sulfate, and the insoluble material was removed by filtration. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 to 0: 1) to obtain N- [1-[[4- (3-hydroxypropyl) phenyl]. Methylamino] -1-oxohexane-2-yl] -3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxamide (241 mg) was obtained.
^{1 1} H-NMR (DMSO-D ₆ , 400MHz) δ: 0.87 (3H, t, J = 7.0 Hz), 1.04 (6H, s), 1.23-1.37 (4H, m), 1.59-1.82 (4H, m) , 2.24 (2H, s), 2.49 (3H, s), 2.55-2.62 (2H, m), 2.65 (2H, s), 3.38-3.44 (2H, m), 4.20-4.33 (2H, m), 4.41 -4.50 (2H, m), 7.11-7.20 (4H, m), 7.47 (1H, d, J = 7.9 Hz), 8.53 (1H, t, J = 6.1 Hz), 11.72 (1H, s).
HRMS (ESI ⁺ ): 482.30238 [M + H] ⁺

Using the corresponding starting materials and reactants, the following Examples 1-2 to 1-149 were obtained by the same method as in Example 1-1, the method described in Step 1-3, or a method similar thereto. ..

2- (3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide) hexanoic acid (50 mg), (S) -1-phenethylamine (20 mg) ) In a solution of N, N-dimethylformamide (2 mL) with 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride (50 mg) at room temperature. Added in. The mixed solution was stirred for 2 hours. Ethyl acetate and water were added to the reaction solution to carry out a liquid separation operation, and the organic layer was separated. The aqueous layer was re-extracted twice with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to separate the two diastereomers, and 3,6,6-trimethyl-4-oxo-N-((S) -1-oxo-1-((S)). -1-phenylethyl) amino) hexane-2-yl) -4,5,6,7-tetrahydro-1H-indole-2-carboxamide and its isomers were isolated.
¹ H-NMR (270 MHz, CDCl ₃ ) δ: 0.90 (3H, t, J = 7.0 Hz), 1.03-1.12 (6H, m), 1.30-1.41 (4H, m), 1.50 (3H, d, J) = 7.1 Hz), 1.68-1.77 (1H, m), 1.88-2.02 (1H, m), 2.32 (2H, s), 2.58 (2H, s), 2.66 (3H, s), 4.56 (1H, dt, J = 7.2, 7.1 Hz), 5.11 (1H, dq, J = 7.6, 7.1 Hz), 6.48 (1H, d, J = 7.2Hz), 6.65 (1H, d, J = 7.6Hz), 7.18-7.35 ( 5H, m), 9.55 (1H, brs).
MS (ESI ⁺ ): 438.42 [M + H] ⁺

3,6,6-trimethyl-4-oxo-N-((R) -1-oxo-1-(((S) -1-phenylethyl) amino) hexane-2-yl) -4,5,6 , 7-Tetrahydro-1H-Indole-2-Carboxamide
¹ H-NMR (270 MHz, CDCl ₃ ) δ: 0.81 (3H, t, J = 6.8 Hz), 1.07 (6H, br, s), 1.18-1.31 (4H, m), 1.46 (3H, d, J) = 6.9 Hz), 1.59-1.75 (1H, m), 1.77-1.93 (1H, m), 2.32 (2H, s), 2.58 (2H, s), 2.66 (3H, s), 4.59 (1H, dt, J = 7.9, 8.0 Hz), 5.11 (1H, dq, J = 7.7, 6.9 Hz), 6.69 (1H, d, J = 7.9 Hz), 6.83 (1H, d, J = 7.7 Hz), 7.21-7.38 ( 5H, m), 9.55 (1H, brs).
MS (ESI ⁺ ): 438.41 [M + H] ⁺

Using the corresponding starting materials and reactants, the following Examples 2-3 to 2-4 were obtained by the same method as in Example 2-1 and the method described in Step 1-3 or a method similar thereto. ..

2- (3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide) hexanoic acid and (R) -2-amino-2-phenylethane-1 -Using ool, N- (1-(((R) -2-hydroxy-1-phenylethyl) amino) -1-oxohexane-2-yl) -3, in the same manner as in Example 2-1. 6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide was obtained.
^{1 1} H-NMR (270 MHz, CDCl ₃ ) δ: 0.80-0.90 (3H, m), 1.00-1.07 (6H, m), 1.21-1.42 (4H, m), 1.62-2.04 (2H, m), 2.29 (2 H, s), 2.50 and 2.53 (2H, s), 2.62 and 2.64 (3H, s), 3.85-4.05 (2H, m), 4.88-5.22 (2H, m), 6.70 and 6.86 (1H, d) , J = 7.3 Hz), 7.19-7.38 (5H, m,), 8.13 and 8.21 (1H, d, J = 7.2 Hz), 9.95 and 10.26 (1H, s).
MS (ESI ⁺ ): 454.36 [M + H] ⁺

Using the corresponding starting material and reactant, the following Example 3-2 was obtained by the same method as in Example 3-1 and the method described in Step 1-3 or a method similar thereto.

2-[(3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carbonyl) amino] hexanoic acid and tert-butyl 3- (5-aminopyridine-2-yl) It was synthesized in the same manner as in Reference Example 1-1 using oxyazetidine-1-carboxylate.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 0.89-0.93 (3H, m), 1.095 (3H, s), 1.101 (3H, s), 1.25-1.33 (4H, m), 1.38-1.43 (2H) , m), 1.44 (9H, s), 2.35 (2H, s), 2.646 (2H, s), 2.654 (3H, s), 3.90-3.98 (2H, m), 4.29 (2H, dd, J = 9.7) , 6.7 Hz), 4.61-4.70 (1H, m), 5.22-5.31 (1H, m), 6.40 (1H, d, J = 7.3 Hz), 6.74 (1H, d, J = 9.1 Hz), 7.92 (1H) , dd, J = 9.1, 2.4 Hz), 8.15 (1H, d, J = 2.4 Hz), 8.45 (1H, s), 9.25 (1H, s).

Using the corresponding starting materials and reactants, the following Reference Examples 68-2 to 68-17 were obtained by the same method as in Reference Example 68-1, the method described in Step 1-3, or a method similar thereto. ..

Under an argon atmosphere, tert-butyl N-[[6-[(dimethylamino) methyl] pyridin-2-yl] methyl] -N-[(2-methylpropan-2-yl) oxycarbonyl] carbamate (170 mg) Trifluoroacetic acid (1.16 mL) was added to the dichloromethane solution (1.16 mL) under ice-cooling, and the reaction mixture was concentrated after stirring at room temperature for 30 minutes. 2-[(3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indol-2-carbonyl) was added to the obtained crude product in N, N-dimethylformamide solution (2.33 mL). ) Amino] Hexanoic acid (156 mg), 1-hydroxybenzotriazole monohydrate (75.4 mg) is added, and N, N-diisopropylethylamine (0.316 mL), 1-ethyl is further added under ice-cooling. -3- (3-Dimethylaminopropyl) carbodiimide hydrochloride (98.2 mg) was added, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the insoluble matter was removed by filtration. After distilling off the solvent, the residue was purified by aminoated silica gel column chromatography (methanol / ethyl acetate = 10%), and the resulting solid was washed with diisopropyl ether and N- [1-[[6-[(dimethylamino)). Methyl] pyridine-2-yl] methylamino] -1-oxohexane-2-yl] -3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxamide (155 mg) ) Was obtained.
¹ H-NMR (DMSO-D ₆ , 400MHz) δ: 0.86 (3H, t, J = 6.7 Hz), 1.01 (6H, s), 1.24-1.37 (4H, m), 1.60-1.71 (1H, m) , 1.72-1.82 (1H, m), 2.15 (6H, s), 2.21 (2H, s), 2.47 (3H, s), 2.63 (2H, s), 3.45 (2H, s), 4.30 (1H, dd , J = 16.3, 6.1 Hz), 4.38 (1H, dd, J = 16.3, 6.1 Hz), 4.45 (1H, td, J = 8.5, 5.4 Hz), 7.14 (1H, d, J = 7.9 Hz), 7.26 (1H, d, J = 7.9 Hz), 7.47 (1H, d, J = 7.9 Hz), 7.70 (1H, t, J = 7.9 Hz), 8.61 (1H, t, J = 5.4 Hz), 11.64 (1H) , s).
HRMS (ESI ⁺ ): 482.31381 [M + H] ⁺

2-[(3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carbonyl) amino] hexanoic acid (500 mg) and N, N'-dicyclohexylcarbodiimide under an argon atmosphere Pentafluorophenol (289 mg) was added to a solution of (339 mg) in ethyl acetate (7.50 mL) at 50 ° C., and the mixture was stirred for 2 hours. After filtering the reaction solution with a cotton swab, the filtrate was distilled off under reduced pressure. Ethyl acetate was added to the residue, washed twice with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the insoluble material was removed by filtration. After distilling off the solvent under reduced pressure, the residue was suspended and washed with diisopropyl ether to cause (2,3,4,5,6-pentafluorophenyl) 2-[(3,6,6-trimethyl-4-oxo-). 5,7-Dihydro-1H-indole-2-carbonyl) amino] hexanoate (414 mg) was obtained.
^{1 1} H-NMR (DMSO-D ₆ , 400MHz) δ: 0.86 (3H, t, J = 7.0 Hz), 1.00 (6H, s), 1.24-1.43 (4H, m), 1.65-1.76 (1H, m) , 1.80-1.89 (1H, m), 2.24 (2H, s), 2.46 (3H, s), 2.65 (2H, s), 4.51-4.57 (1H, m), 11.44 (1H, brs), 12.07 (1H) , s).

Under an argon atmosphere, (2,3,4,5,6-pentafluorophenyl) 2-[(3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carbonyl) amino ] Hexanoate (70.0 mg), 2- (difluoromethyl) aniline (27.6 mg) and N, N-diisopropylethylamine (48.7 μL) in N, N-dimethylacetamide (0.70 mL) solution Was stirred at 50 ° C. for 2 hours. After distilling off the reaction solution under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1 to 0: 1) to obtain N- [1- [2- (difluoromethyl) anilino] -1. -Oxohexane-2-yl] -3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxamide (14.0 mg) was obtained.
^{1 1} H-NMR (DMSO-D ₆ , 400MHz) δ: 0.89 (3H, t, J = 7.0 Hz), 1.01 (6H, s), 1.25-1.45 (4H, m), 1.67-1.89 (2H, m) , 2.21 (2H, s), 2.47 (3H, s), 2.64 (2H, s), 4.47-4.60 (1H, m), 7.02 (1H, t, J = 55.1 Hz), 7.31-7.43 (2H, m) ), 7.54 (1H, t, J = 7.6 Hz), 7.61 (2H, t, J = 7.3 Hz), 9.96 (1H, s), 11.66 (1H, s).
HRMS (ESI ⁺ ): 460.24139 [M + H] ⁺

Using the corresponding starting materials and reactants, the following Examples 5-2 to 5-3 were obtained by the same method as in Example 5-1 and the method described in Step 2-2 or a method similar thereto. ..

In an argon atmosphere, 4-cyclopropyl-2-[(2-methylpropan-2-yl) oxycarbonylamino] butanoic acid (214 mg) and 4-ethyl-6-methylpyridin-3-amine (120 mg) Diisopropylamine (0.299 mL) and 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,] in a solution of N, N-dimethylformamide (4.50 mL) at room temperature. 5-b] Pyridinenium-3-oxide hexafluorophosphate (368 mg) was added, and the mixture was stirred for 120 hours. The reaction mixture was added to water, and the mixture was extracted twice with ethyl acetate. The combined extraction layers were washed in the order of water and saturated brine, dried over anhydrous sodium sulfate, and the insoluble material was removed by filtration. After distilling off the solvent under reduced pressure, the residue was purified by aminoated silica gel column chromatography (hexane: ethyl acetate = 3: 1 to 0: 1) to obtain tert-butyl N- [4-cyclopropyl-1-[((). 4-Ethyl-6-methylpyridine-3-yl) amino] -1-oxobutane-2-yl] carbamate (288 mg) was obtained.
^{1 1} H-NMR (DMSO-D ₆ , 400MHz) δ: -0.06-0.07 (2H, m), 0.32-0.43 (2H, m), 0.56-0.74 (1H, m), 1.09 (3H, t, J = 7.6 Hz), 1.20-1.29 (2H, m), 1.38 (9H, s), 1.60-1.86 (2H, m), 2.40 (3H, s), 2.47-2.54 (2H, m), 4.04-4.13 (1H) , m), 7.03 (1H, d, J = 7.9 Hz), 7.12 (1H, s), 8.20 (1H, s), 9.38 (1H, s).
MS (ESI ⁺ ): 362.2 [M + H] ⁺

Using the corresponding starting materials and reactants, the following Reference Examples 70-2 to 70-58 were obtained by the same method as in Reference Example 70-1, the method described in Step 3-1 or a method similar thereto. ..

Under an argon atmosphere, tert-butyl N-[[6-[[2- (dimethylamino) ethyl-methylamino] methyl] pyridine-2-yl] methyl] -N-[(2-methylpropan-2-yl) Trifluoroacetic acid (0.663 mL) was added to a dichloromethane solution (0.663 mL) of oxycarbonyl] carbamate (112 mg) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes, and then the reaction mixture was concentrated under reduced pressure. .. 2-[(2-Methylpropan-2-yl) oxycarbonylamino] hexanoic acid (61.3 mg), 1-hydroxy in the obtained crude product N, N-dimethylformamide solution (1.33 mL) After adding benzotriazole monohydrate (43.0 mg), N, N-diisopropylethylamine (0.180 mL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride under ice-cooling (56.0 mg) was added, and the mixture was stirred at room temperature for 7 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the insoluble matter was removed by filtration. After distilling off the solvent, the residue was purified by amination silica gel column chromatography (ethyl acetate) and tert-butyl N- [1-[[6-[[2- (dimethylamino) ethyl-methylamino] methyl] pyridine-. 2-Il] methylamino] -1-oxohexane-2-yl] carbamate (37.7 mg) was obtained.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 0.88 (3H, t, J = 6.7 Hz), 1.29-1.36 (4H, m), 1.44 (9H, s), 1.55-1.65 (1H, m), 1.82-1.90 (1H, m), 2.23 (6H, s), 2.27 (3H, s), 2.41-2.51 (2H, m), 2.55-2.62 (2H, m), 3.68 (2H, s), 4.14- 4.22 (1H, m), 4.51 (1H, dd, J = 16.3, 4.8 Hz), 4.59 (1H, dd, J = 16.3, 4.8 Hz), 5.34-5.56 (1H, m), 7.13 (1H, d, J = 7.9 Hz), 7.28 (1H, d, J = 7.9 Hz), 7.43 (1H, brs), 7.61 (1H, t, J = 7.9 Hz).
HRMS (ESI ⁺ ): 436.32827 [M + H] ⁺

Dichloromethane of tert-butyl N- [4-cyclopropyl-1-[(4-ethyl-6-methylpyridine-3-yl) amino] -1-oxobutane-2-yl] carbamate (288 mg) under an argon atmosphere. Trifluoroacetic acid (4.00 mL) was added to the (4.00 mL) solution at room temperature, and the mixture was stirred for 20 minutes. In a solution of N, N-dimethylformamide (4.00 mL) of the residue obtained by distilling off the solvent of the reaction solution under reduced pressure at room temperature, 3,6,6-trimethyl-4-oxo-5,7-dihydro-1H- Indol-2-carboxylic acid (176 mg), 1-hydroxybenzotriazole monohydrate (146 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (168 mg) and N, N -Diisopropylethylamine (0.679 mL) was added, and the mixture was stirred for 51 hours. The reaction mixture was added to water, and the mixture was extracted twice with ethyl acetate. The combined extraction layers were washed in the order of water and saturated brine, dried over anhydrous sodium sulfate, and the insoluble material was removed by filtration. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 to 0: 1) to obtain N- [4-cyclopropyl-1-[(4-ethyl-6). -Methylpyridine-3-yl) amino] -1-oxobutane-2-yl] -3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxamide (231 mg) Obtained.
¹ H-NMR (DMSO-D ₆ , 400MHz) δ: -0.02-0.06 (2H, m), 0.36-0.45 (2H, m), 0.65-0.80 (1H, m), 1.01 (6H, s), 1.09 (3H, t, J = 7.3 Hz), 1.27-1.36 (2H, m), 1.77-2.01 (2H, m), 2.21 (2H, s), 2.41 (3H, s), 2.47 (3H, s), 2.52 (2H, q, J = 7.3 Hz), 2.63 (2H, s), 4.59-4.70 (1H, m), 7.13 (1H, s), 7.58 (1H, d, J = 7.9 Hz), 8.24 (1H) , s), 9.62 (1H, s), 11.66 (1H, s).
HRMS (ESI ⁺ ): 465.28697 [M + H] ⁺

From Example 6-2 below, using the corresponding starting materials and reactants, by the same method as in Example 6-1 or the method described in Step 3-2 or Step 3-3, or a method similar thereto. 6-107 was obtained.

Under an argon atmosphere, a solution of tert-butyl N- [1-[(6-methoxypyridin-3-yl) amino] -1-oxohexane-2-yl] carbamate (61.8 mg) in dichloromethane (0.458 mL) ) Was added with trifluoroacetic acid (0.458 mL), and the mixture was stirred at room temperature for 30 minutes, and then the reaction solution was concentrated under reduced pressure. 2,2-Diphenylacetyl chloride (46.4 mg) and N, N-diisopropylethylamine (0.125 mL) were added to the obtained crude product in dichloromethane (0.916 mL), and the mixture was stirred at room temperature for 24 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the insoluble matter was removed by filtration. After distilling off the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1), and the resulting solid was washed with diisopropyl ether to 2-[(2,2-diphenylacetyl) amino] -N. -(6-methoxypyridine-3-yl) hexaneamide (64.7 mg) was obtained.
^{1 1} H-NMR (DMSO-D ₆ , 400MHz) δ: 0.79 (3H, t, J = 6.7 Hz), 1.17-1.28 (4H, m), 1.54-1.73 (2H, m), 3.79 (3H, s) , 4.41 (1H, td, J = 7.9, 5.4 Hz), 5.13 (1H, s), 6.78 (1H, d, J = 9.1 Hz), 7.17-7.30 (10H, m), 7.86 (1H, dd, J) = 9.1, 2.4 Hz), 8.33 (1H, d, J = 2.4 Hz), 8.58 (1H, d, J = 7.9 Hz), 10.12 (1H, s).
HRMS (ESI ⁺ ): 43.222900 [M + H] ⁺

Under an argon atmosphere, a solution of tert-butyl N- [4-cyclopropyl-1-[(6-methoxypyridin-3-yl) amino] -1-oxobutane-2-yl] carbamate (50.8 mg) in dichloromethane (50.8 mg). Trifluoroacetic acid (0.363 mL) was added to 0.363 mL), and the mixture was stirred at room temperature for 30 minutes, and then the reaction solution was concentrated under reduced pressure. 2-Phenylacetyl chloride (0.021 mL) and N, N-diisopropylethylamine (0.099 mL) were added to the obtained crude product in dichloromethane (0.727 mL), and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the insoluble matter was removed by filtration. After distilling off the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2), and the resulting solid was washed with diisopropyl ether and 4-cyclopropyl-N- (6-methoxypyridin-3-3). Il) -2-[(2-phenylacetyl) amino] butaneamide (32.3 mg) was obtained.
¹ H-NMR (DMSO-D ₆ , 400MHz) δ: -0.11--0.02 (2H, m), 0.34 (2H, d, J = 7.9 Hz), 0.59-0.68 (1H, m), 1.12-1.22 ( 2H, m), 1.63-1.82 (2H, m), 3.44 (1H, d, J = 13.9 Hz), 3.51 (1H, d, J = 13.9 Hz), 3.79 (3H, s), 4.37 (1H, td , J = 7.9, 5.4 Hz), 6.78 (1H, d, J = 8.5 Hz), 7.15-7.29 (5H, m), 7.87 (1H, dd, J = 8.5, 2.4 Hz), 8.31-8.38 (2H, m), 10.07 (1H, s).
HRMS (ESI ⁺ ): 368.19644 [M + H] ⁺

In an argon atmosphere, ethanol (0.50 mL) and tetrahydrofuran (0.50 mL) of benzyl N- [1-oxo-1- (quinoline-4-ylamino) hexane-2-yl] carbamate (76.7 mg) To the mixed solution, 10% palladium carbon (15.3 mg) was added at room temperature, and the mixture was stirred under a hydrogen atmosphere for 5 hours, and then hydrogen in the reaction vessel was replaced with argon. After filtering the reaction solution with Celite, the solvent of the filtrate and the like were distilled off under reduced pressure. After dissolving the residue in N, N-dimethylformamide (1.00 mL), 3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indol-2-carboxylic acid (47) at room temperature. .5 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (47.0 mg), 1-hydroxybenzotriazole (46.4 mg) and N, N-diisopropylethylamine (71.0 μL) ) Was added, and the mixture was stirred for 4 hours. The reaction mixture was added to water, and the mixture was extracted twice with ethyl acetate. The combined extraction layers were washed twice with saturated brine, dried over anhydrous sodium sulfate, and the insoluble material was removed by filtration. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: methanol = 99: 1 to 11: 1) to result in 3,6,6-trimethyl-4-oxo-N- [1-]. Oxo-1- (quinoline-4-ylamino) hexane-2-yl] -5,7-dihydro-1H-indole-2-carboxamide (78.0 mg) was obtained.
¹ H-NMR (DMSO-D ₆ , 400MHz) δ: 0.89 (3H, t, J = 7.3 Hz), 1.02 (6H, s), 1.27-1.49 (4H, m), 1.73-1.95 (2H, m) , 2.22 (2H, s), 2.50 (3H, s), 2.64 (2H, s), 4.80-4.94 (1H, m), 7.65 (1H, t, J = 7.9 Hz), 7.73-7.80 (2H, m) ), 8.00 (1H, d, J = 7.6 Hz), 8.04 (1H, d, J = 5.2 Hz), 8.34 (1H, d, J = 7.6 Hz), 8.80 (1H, d, J = 5.2 Hz), 10.44 (1H, s), 11.70 (1H, s).
HRMS (ESI ⁺ ): 461.25486 [M + H] ⁺

Using the corresponding starting material and reactant, the following Example 9-2 can be prepared by the same method as in Example 9-1, the method described in Step 3-2 or Step 3-3, or a method similar thereto. Obtained.

Benzyl N- [1-[[6- (oxetane-3-yloxy) pyridin-3-yl] amino] -1-oxohexane-2-yl] carbamate (100 mg) in ethanol (1.50) under an argon atmosphere. mL) To the solution, 10% palladium carbon (20.0 mg) was added at room temperature, and the mixture was stirred under a hydrogen atmosphere for 2 hours, and then hydrogen in the reaction vessel was replaced with argon. After filtering the reaction solution with Celite, diisopropylamine (61.7 μL) and 2-phenylacetyl chloride were added to a solution of the residue obtained by distilling off the solvent of the filtrate under reduced pressure in dichloromethane (2.50 mL) at 0 ° C. (32.0 μL) was added, and the mixture was stirred for 1.5 hours. The reaction mixture was added to water, and the mixture was extracted twice with ethyl acetate. The combined extraction layers were washed in the order of water and saturated brine, dried over anhydrous sodium sulfate, and the insoluble material was removed by filtration. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1 to 0: 1) to obtain N- [6- (oxetane-3-yloxy) pyridine-3-yl. ] -2-[(2-Phenylacetyl) amino] hexaneamide (80.0 mg) was obtained.
¹ H-NMR (DMSO-D ₆ , 400MHz) δ: 0.82 (3H, t, J = 6.7 Hz), 1.14-1.35 (4H, m), 1.50-1.76 (2H, m), 3.45 (1H, d, J = 13.9 Hz), 3.51 (1H, d, J = 13.9 Hz), 4.30-4.41 (1H, m), 4.52 (2H, dd, J = 7.6, 5.1 Hz), 4.81-4.90 (2H, m), 5.46-5.52 (1H, m), 6.87 (1H, d, J = 8.5 Hz), 7.16-7.30 (5H, m), 7.92 (1H, dd, J = 8.5, 2.4 Hz), 8.29 (1H, d, J = 2.4 Hz), 8.37 (1H, d, J = 7.9 Hz), 10.11 (1H, s).
HRMS (ESI ⁺ ): 398.20803 [M + H] ⁺

Benzyl N- [1-[[6- (1-methylpiperidin-4-yl) oxypyridin-3-yl] amino] -1-oxohexane-2-yl] carbamate was used in the same manner as in Reference Example 5. Synthesized.
^{1 1} H-NMR (DMSO-D ₆ , 400MHz) δ: 0.85 (3H, t, J = 7.0 Hz), 1.20-1.48 (5H, m), 1.54-1.68 (3H, m), 1.87-1.96 (2H, m), 2.06-2.18 (5H, m), 2.55-2.66 (2H, m), 3.25 (1H, dd, J = 7.9, 5.4 Hz), 4.83-4.94 (1H, m), 6.72 (1H, d, J = 9.1 Hz), 7.92 (1H, dd, J = 9.1, 2.4 Hz), 8.34 (1H, d, J = 2.4 Hz).
MS (ESI ⁺ ): 321.2 [M + H] ⁺

Using the corresponding starting material and reactant, the following Reference Example 72-2 was obtained by the same method as in Reference Example 72-1, the method described in Step 3-2, or a method similar thereto.

2-Amino-N- [in an N, N-dimethylformamide solution (0.780 mL) of 2-methyl-4- (4-methylpiperazin-1-yl) benzoic acid (36.5 mg) under an argon atmosphere. 6- (1-Methylpiperidin-4-yl) Oxypyridine-3-yl] Hexamide (50.0 mg), 1-hydroxybenzotriazole monohydrate (25.3 mg) are added, and then ice-cooled. Underneath, N, N-diisopropylethylamine (0.040 mL) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (33.0 mg) were added, and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the insoluble matter was removed by filtration. After distilling off the solvent, the residue was purified by aminoated silica gel column chromatography (ethyl acetate: methanol = 9: 1), and the resulting solid was washed with hexane: ethyl acetate = 5: 1 and 2-methyl-4- (2-methyl-4- ( 4-Methylpiperazin-1-yl) -N- [1-[[6- (1-methylpiperidin-4-yl) oxypyridin-3-yl] amino] -1-oxohexane-2-yl] benzamide ( 26.5 mg) was obtained.
¹ H-NMR (DMSO-D ₆ , 400MHz) δ: 0.87 (3H, t, J = 6.7 Hz), 1.25-1.38 (4H, m), 1.57-1.75 (4H, m), 1.88-1.96 (2H, m), 2.07-2.13 (2H, m), 2.16 (3H, s), 2.20 (3H, s), 2.31 (3H, s), 2.42 (4H, t, J = 4.8 Hz), 2.57-2.64 (2H) , m), 3.17 (4H, t, J = 4.8 Hz), 4.45 (1H, td, J = 7.9, 6.1 Hz), 4.85-4.93 (1H, m), 6.72-6.76 (3H, m), 7.31 ( 1H, d, J = 9.1 Hz), 7.89 (1H, dd, J = 9.1, 2.4 Hz), 8.11 (1H, d, J = 7.9 Hz), 8.32 (1H, d, J = 2.4 Hz), 10.05 ( 1H, s).
HRMS (ESI ⁺ ): 537.35620 [M + H] ⁺

Using the corresponding starting materials and reactants, the following Examples 11-2 to 11-11 were obtained by the same method as in Example 11-1, the method described in Step 3-3, or a method similar thereto. ..

Under an argon atmosphere, pyridine (1.00 mL) in a solution of 2-amino-N- [6- (1-methylpiperidin-4-yl) oxypyridine-3-yl] hexaneamide (50.0 mg) in tetrahydrofuran (1.00 mL). 18.9 μL) and 2,2-diphenylacetyl chloride (39.7 mg) were added at 0 ° C., and after stirring at room temperature for 3 hours, the reaction solution was subjected to amination silica gel column chromatography (methanol: ethyl acetate = 0). : By purifying with 1 to 1: 9), 2-[(2,2-diphenylacetyl) amino] -N- [6- (1-methylpiperidin-4-yl) oxypyridin-3-yl] hexane Amide (67.0 mg) was obtained.
^{1 1} H-NMR (DMSO-D ₆ , 400MHz) δ: 0.79 (3H, t, J = 7.0 Hz), 1.10-1.31 (4H, m), 1.50-1.75 (4H, m), 1.86-1.96 (2H, m), 2.07-2.18 (5H, m), 2.55-2.64 (2H, m), 4.35-4.46 (1H, m), 4.83-4.93 (1H, m), 5.13 (1H, s), 6.73 (1H, m) d, J = 9.1 Hz), 7.16-7.35 (10H, m), 7.85 (1H, dd, J = 9.1, 3.0 Hz), 8.29 (1H, d, J = 3.0 Hz), 8.57 (1H, d, J) = 7.3 Hz), 10.10 (1H, s).
HRMS (ESI ⁺ ): 515.30139 [M + H] ⁺

Using the corresponding starting material and reactant, the following Example 12-2 was obtained by the same method as in Example 12-1, the method described in Step 3-3, or a method similar thereto.

3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxylic acid and tert-butyl N- [6- (2-aminohexanoylamino) -4-methyl-1, 3-Benzothiazole-2-yl] carbamate was used and synthesized in the same manner as in Example 6-1.
^{1 1} H-NMR (DMSO-D ₆ , 400MHz) δ: 0.87 (3H, t, J = 7.0 Hz), 1.01 (6H, s), 1.27-1.42 (4H, m), 1.48 (9H, s), 1.66 -1.86 (2H, m), 2.22 (2H, s), 2.47 (3H, s), 2.64 (2H, s), 3.30 (3H, s), 4.52-4.60 (1H, m), 7.32 (1H, d) , J = 1.8 Hz), 7.57 (1H, d, J = 7.3 Hz), 8.09 (1H, d, J = 1.8 Hz), 10.15 (1H, s), 11.68 (1H, s), 11.72 (1H, s) ).
MS (ESI ⁺ ): 596.3 [M + H] ⁺

Using the corresponding starting materials and reactants, the following Reference Examples 73-2 to 73 can be carried out by the same method as in Reference Example 73-1, the method described in Step 3-2 or Step 3-3, or a method similar thereto. I got -4.

Synthesized with tert-butyl (4-cyclopropyl-1-oxo-1-(((S) -1-phenylethyl) amino) butane-2-yl) carbamate in the same manner as in Example 6-1 and N -((S) -4-cyclopropyl-1-oxo-1-(((S) -1-phenylethyl) amino) butane-2-yl) -3,6,6-trimethyl-4-oxo-4 , 5,6,7-Tetrahydro-1H-indole-2-carboxamide and its isomers were obtained.
^{1 1} H-NMR (270 MHz, CDCl ₃ ) δ: -0.23--0.07 (2H, m), 0.23-0.43 (2H, m), 0.45-0.65 (1H, m), 0.93-1.29 (8H, m) , 1.38 (3H, d, J = 6.9 Hz), 1.65-2.01 (2H, m), 2.29 (2H, s), 2.51 (2H, s), 2.65 (3H, s), 4.69 (1H, dd, J = 13.5, 7.6 Hz), 4.99-5.10 (1H, m), 7.18-7.40 (7H, m), 10.34 (1H, s).
MS (ESI ⁺ ): 450.37 [M + H] ⁺

N-((R) -4-cyclopropyl-1-oxo-1-(((S) -1-phenylethyl) amino) butane-2-yl) -3,6,6-trimethyl-4-oxo- 4,5,6,7-Tetrahydro-1H-Indole-2-Carboxamide
^{1 1} H-NMR (270 MHz, CDCl ₃ ) δ: -0.05-0.10 (2H, m), 0.38-0.50 (2H, m), 0.57-0.80 (1H, m), 1.08 (6H, s), 1.17- 1.42 (2H, m), 1.50 (3H, d, J = 6.9 Hz), 1.72-1.92 (1H, m), 1.97-2.18 (1H, m), 2.32 (2H, s), 2.57-2.64 (5H, s) m), 4.48-4.68 (1H, m), 5.02-5.19 (1H, m), 6.34 (1H, d, J = 7.6 Hz), 6.50 (1H, d, J = 7.9 Hz), 7.17-7.40 (5H) , m), 9.28 (1H, s).
MS (ESI ⁺ ): 450.37 [M + H] ⁺

Using the corresponding starting materials and reactants, the following Examples 13-3 to 13 can be carried out by the same method as in Example 13-1, the method described in Step 3-2 or Step 3-3, or a method similar thereto. I got -6.

Under an argon atmosphere, a solution of tert-butyl N- [1- (2-bromo-4-methylanilino) -4-cyclopropyl-1-oxobutane-2-yl] carbamate (200 mg) in 1,2-dimethoxyethane (2). .43 mL) with 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.100 mL), 2 mol / L sodium carbonate aqueous solution (0.730 mL), bis (. Triphenylphosphine) palladium (II) dichloride (34.1 mg) was added, and the mixture was stirred at 80 ° C. for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the insoluble matter was removed by filtration. After distilling off the solvent, the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0% -33%), and tert-butyl N- [4-cyclopropyl-1- (2-ethenyl-4-methylanilino)-. 1-Oxobutane-2-yl] carbamate (86.7 mg) was obtained.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 0.03-0.07 (2H, m), 0.43-0.48 (2H, m), 0.66-0.72 (1H, m), 1.30-1.38 (2H, m), 1.47 (9H, s), 1.74-1.81 (1H, m), 2.04-2.14 (1H, m), 2.32 (3H, s), 4.15-4.30 (1H, m), 4.85-5.05 (1H, m), 5.36 (1H, d, J = 10.9 Hz), 5.66 (1H, d, J = 17.0 Hz), 6.78 (1H, dd, J = 17.0, 10.9 Hz), 7.09 (1H, dd, J = 8.5, 1.8 Hz) , 7.25 (1H, d, J = 1.8 Hz), 7.69 (1H, d, J = 8.5 Hz), 7.93 (1H, brs).
HRMS (ESI ⁺ ): 359.23318 [M + H] ⁺

Using the corresponding starting material and reactant, the following Reference Example 74-2 was obtained by the same method as in Reference Example 74-1, the method described in Step 36-1, or a method similar thereto.

Under an argon atmosphere, a mixed solution of tert-butyl N- [4-cyclopropyl-1- (2-ethenyl-4-methylanilino) -1-oxobutane-2-yl] carbamate (86.7 mg) in tetrahydrofuran-ethanol (1). After adding 5% palladium carbon (17.3 mg) to .21 mL, 1: 1), the mixture was stirred at room temperature for 9 hours under a hydrogen atmosphere. After replacing the inside of the reaction system with an argon atmosphere, the reaction solution was filtered through Celite. After distilling off the solvent, the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0% -30%) and tert-butyl N- [4-cyclopropyl-1- (2-ethyl-4-methylanilino)-. 1-Oxobutane-2-yl] carbamate (76.1 mg) was obtained.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 0.03-0.07 (2H, m), 0.43-0.48 (2H, m), 0.65-0.74 (1H, m), 1.21 (3H, t, J = 7.3 Hz) ), 1.31-1.38 (2H, m), 1.46 (9H, s), 1.73-1.83 (1H, m), 2.07-2.15 (1H, m), 2.30 (3H, s), 2.56 (2H, q, J) = 7.3 Hz), 4.15-4.30 (1H, m), 4.95 (1H, brs), 6.99-7.03 (2H, m), 7.66 (1H, d, J = 8.6 Hz), 7.87 (1H, brs).
HRMS (ESI ⁺ ): 361.24877 [M + H] ⁺

Using the corresponding starting material and reactant, the following Reference Example 75-2 was obtained by the same method as in Reference Example 75-1, the method described in Step 36-2, or a method similar thereto.

Under an argon atmosphere, a solution of tert-butyl N- [4-cyclopropyl-1- (2-ethyl-4-methylanilino) -1-oxobutane-2-yl] carbamate (76.1 mg) in dichloromethane (0.528 mL) ) Was added with trifluoroacetic acid (0.528 mL), and the mixture was stirred at room temperature for 30 minutes, and then the reaction solution was concentrated under reduced pressure. In the obtained crude product N, N-dimethylformamide solution (1.06 mL), 3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indol-2-carboxylic acid (46. 7 mg), 1-hydroxybenzotriazole monohydrate (38.7 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (44.5 mg), N, N-diisopropylethylamine (38.7 mg) 0.144 mL) was added, and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the insoluble matter was removed by filtration. After distilling off the solvent, the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 10% -50%), and the resulting solid was washed with diisopropyl ether and N- [4-cyclopropyl-1- (2-). Ethyl-4-methylanilino) -1-oxobutane-2-yl] -3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxamide (61.6 mg) was obtained. ..
^{1 1} H-NMR (DMSO-D ₆ , 400MHz) δ: 0.00-0.05 (2H, m), 0.39-0.44 (2H, m), 0.69-0.77 (1H, m), 1.02 (6H, s), 1.08 ( 3H, t, J = 7.3 Hz), 1.28-1.35 (2H, m), 1.81-1.99 (2H, m), 2.22 (2H, s), 2.26 (3H, s), 2.48 (3H, s), 2.49 -2.55 (2H, m), 2.64 (2H, s), 4.65 (1H, td, J = 7.9, 6.1 Hz), 6.97 (1H, dd, J = 7.9, 1.8 Hz), 7.04 (1H, d, J) = 1.8 Hz), 7.16 (1H, d, J = 7.9 Hz), 7.56 (1H, d, J = 7.9 Hz), 9.41 (1H, s), 11.69 (1H, br s).
HRMS (ESI ⁺ ): 464.29052 [M + H] ⁺

Using the corresponding starting material and reactant, the following Example 14-2 is obtained by the same method as in Example 14-1, the method described in Step 3-2 or Step 3-3, or a method similar thereto. It was.

Under an argon atmosphere, a solution of tert-butyl N-[(2S) -4-cyclopropyl-1- (4-iodoanilino) -1-oxobutane-2-yl] carbamate (275 mg) in N, N-dimethylformamide (1). After adding zinc cyanide (363 mg) to .55 mL) and stirring at 90 ° C. for 15 minutes, dibenzylideneacetone palladium (0) (72.0 mg), 2-dicyclohexylphosphino-2', 6'- Dimethoxybiphenyl (51.0 mg) was added, and the temperature was 90 ° C. for 3 hours, and then dibenzylideneacetone palladium (0) (72.0 mg), 2-dicyclohexylphosphino-2', 6'-dimethoxybiphenyl (51.0) mg) was added, and the mixture was stirred at 90 ° C. for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the insoluble matter was removed by filtration. After distilling off the solvent, the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 8% -33%) and tert-butyl N-[(2S) -1- (4-cyanoanilino) -4-cyclopropyl-. 1-Oxobutane-2-yl] carbamate (145 mg) was obtained.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: -0.01-0.03 (2H, m), 0.41-0.44 (2H, m), 0.61-0.69 (1H, m), 1.27-1.32 (2H, m), 1.43 (9H, s), 1.68-1.78 (1H, m), 2.03-2.08 (1H, m), 4.16-4.22 (1H, m), 4.88 (1H, brs), 7.55 (2H, d, J = 8.5) Hz), 7.60 (2H, d, J = 8.5 Hz), 8.79 (1H, brs).
HRMS (ESI ⁺ ): 344.19695 [M + H] ⁺

Using the corresponding starting material and reactant, the following Reference Example 76-2 was obtained by the same method as in Reference Example 76-1, the method described in Step 37-1, or a method similar thereto.

Under an argon atmosphere, tert-butyl N-[(2S) -1- (4-cyanoanilino) -4-cyclopropyl-1-oxobutane-2-yl] carbamate (145 mg) in a dichloromethane solution (1.06 mL). After adding trifluoroacetic acid (1.06 mL) and stirring at room temperature for 30 minutes, the reaction solution was concentrated under reduced pressure. In the obtained crude product N, N-dimethylformamide solution (2.11 mL), 3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indol-2-carboxylic acid (93. 4 mg), 1-hydroxybenzotriazole monohydrate (77.6 mg), N, N-diisopropylethylamine (0.287 mL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride ( 88.9 mg) was added, and the mixture was stirred at room temperature for 17 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the insoluble matter was removed by filtration. After distilling off the solvent, the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 10% -66%), and the resulting solid was washed with diisopropyl ether to N-[(2S) -1- (4-cyanoanilino). ) -4-Cyclopropyl-1-oxobutane-2-yl] -3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxamide (150 mg) was obtained.
¹ H-NMR (DMSO-D ₆ , 400MHz) δ: -0.01-0.02 (2H, m), 0.36-0.40 (2H, m), 0.66-0.74 (1H, m), 1.00 (6H, s), 1.21 -1.33 (2H, m), 1.77-1.90 (2H, m), 2.20 (2H, s), 2.44 (3H, s), 2.62 (2H, s), 4.55 (1H, td, J = 7.9, 5.4 Hz ), 7.71 (1H, d, J = 7.9 Hz), 7.76 (2H, d, J = 9.1 Hz), 7.79 (2H, d, J = 9.1 Hz), 10.58 (1H, s), 11.66 (1H, s) ).
HRMS (ESI ⁺ ): 447.23893 [M + H] ⁺

Using the corresponding starting materials and reactants, the following Examples 15-2 to 15 can be carried out by the same method as in Example 15-1, the method described in Step 3-2 or Step 3-3, or a method similar thereto. I got -4.

Methyl 4-[[2-[(2-methylpropan-2-yl) oxycarbonylamino]] in a tetrahydrofuran solution (0.760 mL) of lithium aluminum hydride (26.7 mg) under ice-cooling under an argon atmosphere. A solution of hexanoylamino] methyl] benzoate (133 mg) in tetrahydrofuran (1.00 mL) was added, and the mixture was stirred at room temperature for 3 hours. Water (0.027 mL), 15% aqueous sodium hydroxide solution (0.027 mL), and water (0.080 mL) were added to the reaction mixture, and the mixture was filtered through Celite. After distilling off the solvent, the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 50%) and tert-butyl N- [1-[[4- (hydroxymethyl) phenyl] methylamino] -1-oxohexane). -2-Il] Carbamate (81.4 mg) was obtained.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 0.87 (3H, t, J = 6.7 Hz), 1.28-1.33 (4H, m), 1.40 (9H, s), 1.55-1.61 (1H, m), 1.80-1.89 (1H, m), 4.03 (1H, brs), 4.42 (2H, s), 4.66 (2H, s), 4.93 (1H, brs), 6.40 (1H, brs), 7.24 (2H, d, J = 7.9 Hz), 7.30 (2H, d, J = 7.9 Hz).
HRMS (ESI ⁺ ): 351.22875 [M + H] ⁺

Dichloromethane solution (0.581 mL) of tert-butyl N- [1-[[4- (hydroxymethyl) phenyl] methylamino] -1-oxohexane-2-yl] carbamate (81.4 mg) under an argon atmosphere. ) Was added with trifluoroacetic acid (0.581 mL), and the mixture was stirred at room temperature for 30 minutes, and then the reaction solution was concentrated under reduced pressure. In the obtained crude product N, N-dimethylformamide solution (1.16 mL), 3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indol-2-carboxylic acid (51. 3 mg), 1-hydroxybenzotriazole monohydrate (42.7 mg), N, N-diisopropylethylamine (0.158 mL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (3 mg) 48.9 mg) was added, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the insoluble matter was removed by filtration. After distilling off the solvent, the residue was purified by silica gel column chromatography (ethyl acetate), and N- [1-[[4- (hydroxymethyl) phenyl] methylamino] -1-oxohexane-2-yl] -3, 6,6-trimethyl-4-oxo-5,7-dihydro-1H-indol-2-carboxamide (73.8 mg) was obtained.
¹ H-NMR (DMSO-D ₆ , 400MHz) δ: 0.84 (3H, t, J = 7.0 Hz), 1.01 (6H, s), 1.24-1.31 (4H, m), 1.59-1.77 (2H, m) , 2.21 (2H, s), 2.46 (3H, s), 2.63 (2H, s), 4.23 (1H, dd, J = 15.1, 6.1 Hz), 4.29 (1H, dd, J = 15.1, 6.1 Hz), 4.40-4.43 (1H, m), 4.44 (2H, d, J = 5.4 Hz), 5.12 (1H, t, J = 5.4 Hz), 7.19 (2H, d, J = 7.9 Hz), 7.23 (2H, d) , J = 7.9 Hz), 7.48 (1H, d, J = 7.9 Hz), 8.54 (1H, t, J = 6.1 Hz), 11.72 (1H, s).
HRMS (ESI ⁺ ): 454.27086 [M + H] ⁺

Dissolve tert-butyl (S)-(1-oxo-1- (phenylamino) hexane-2-yl) carbamate (194 mg) in dichloromethane (10 mL), add trifluoroacetic acid (1 mL) overnight. Stirred. A 2N aqueous sodium hydroxide solution was added to adjust the pH from 13 to 14, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (dissolved in 10 mL, borane-tetrahydrofuran complex (1 M tetrahydrofuran solution) (2.3 mL) was added and stirred at 75 ° C. for 1 day. 2N hydrochloric acid aqueous solution (1 mL) was added and stirred at 75 ° C. for 1 hour. , 2N aqueous sodium hydroxide solution was added to adjust the pH from 13 to 14, extracted 3 times with dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. (S) -N1-phenylhexane-1,2-diamine (116 mg). ) Was obtained.
^{1 1} H-NMR (CDCl ₃ , 270 MHz) δ: 0.92 (3H, t, J = 6.9 Hz), 1.25-1.59 (6H, m), 2.83 (1H, dd, J = 11.9, 8.2 Hz), 2.89- 3.03 (1H, m), 3.18 (1H, dd, J = 11.9, 3.6 Hz), 4.10 (1H, br, s), 6.58-6.73 (3H, m), 7.10-7.22 (2H, m).
MS (ESI ⁺ ): 193.23 [M + H] ⁺

Using the corresponding starting materials and reactants, the following Reference Example 78-2 can be prepared by the same method as in Reference Example 78-1, the method described in Step 3-2 and Step 46-1 or a method similar thereto. Obtained.

Same as Example 6-1 using 3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxylic acid and (S) -N1-phenylhexane-1,2-diamine. (S) -3,6,6-trimethyl-4-oxo-N- (1- (phenylamino) hexane-2-yl) -4,5,6,7-tetrahydro-1H-indole -2-Carboxamide (153 mg) was obtained.
^{1 1} H-NMR (CDCl ₃ , 270 MHz) δ: 0.92 (3H, t, J = 7.1 Hz), 1.08 (6H, s), 1.30-1.51 (4H, m), 1.53-1.82 (2H, m), 2.32 (2H, s), 2.54 (3H, s), 2.65 (2H, s), 3.38-3.20 (2H, m), 3.99-4.20 (1H, m), 4.27-4.49 (1H, m), 5.77 ( 1H, d, J = 8.6 Hz), 6.53-6.76 (3H, m), 7.07-7.22 (2H, m), 9.84 (1H, brs).
MS (ESI ⁺ ): 396.59 [M + H] ⁺

Using the corresponding starting material and reactant, the following Example 17-2 was obtained by the same method as in Example 17-1, the method described in Step 46-2, or a method similar thereto.

N- [1- [3- (Hydroxymethyl) anilino] -1-oxohexane-2-yl] -3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole under an argon atmosphere Triphenylphosphine (86.0 mg) and carbon tetrabromide (127 mg) were added to a mixed solution of tetrahydrofuran-dichloromethane (1.37 mL, 1: 1) of -2-carboxamide (120 mg) at room temperature, and at room temperature. The mixture was stirred for 7 hours. After concentrating the reaction solution under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 8% -66%) and N- [1- [3- (bromomethyl) anilino] -1-oxohexane. -2-Il] -3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxamide (85.1 mg) was obtained.
¹ H-NMR (DMSO-D ₆ , 400MHz) δ: 0.88 (3H, t, J = 6.7 Hz), 1.03 (6H, s), 1.29-1.37 (4H, m), 1.70-1.83 (2H, m) , 2.23 (2H, s), 2.48 (3H, s), 2.65 (2H, s), 4.55 (1H, td, J = 7.9, 4.9 Hz), 4.68 (2H, s), 7.14 (1H, d, J) = 7.9 Hz), 7.30 (1H, t, J = 7.9 Hz), 7.53 (1H, d, J = 7.9 Hz), 7.60 (1H, d, J = 7.9 Hz), 7.75 (1H, s), 10.22 ( 1H, s), 11.68 (1H, s).
HRMS (ESI ⁺ ): 502.17119 [M + H] ⁺

Using the corresponding starting materials and reactants, the following Reference Examples 79-2 to 79-3 were obtained by the same method as in Reference Example 79-1, the method described in Step 4-1 or a method similar thereto. ..

Under an argon atmosphere, N- [1- [3- (bromomethyl) anilino] -1-oxohexane-2-yl] -3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole- To a solution of 2-carboxamide (42.5 mg) in N, N-dimethylformamide (0.211 mL), add dimethylamine (0.047 mL, 2 mol / L tetrahydrofuran solution) and potassium carbonate (12.9 mg). , Stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the insoluble matter was removed by filtration. After distilling off the solvent, the residue was purified by aminoated silica gel column chromatography (ethyl acetate: methanol = 1: 0-4: 1), and the resulting solid was washed with diisopropyl ether and N- [1- [3- []. (Dimethylamino) Methyl] Anilino] -1-oxohexane-2-yl] -3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxamide (14.3 mg) Got
¹ H-NMR (DMSO-D ₆ , 400MHz) δ: 0.88 (3H, t, J = 6.7 Hz), 1.02 (6H, s), 1.32-1.39 (4H, m), 1.70-1.78 (2H, m) , 2.13 (6H, s), 2.23 (2H, s), 2.48 (3H, s), 2.65 (2H, s), 3.34 (2H, s), 4.54 (1H, td, J = 8.6, 4.9 Hz), 6.96 (1H, d, J = 7.3 Hz), 7.24 (1H, t, J = 7.3 Hz), 7.52 (1H, d, J = 8.6 Hz), 7.56-7.62 (2H, m), 10.10 (1H, s) ), 11.71 (1H, s).
HRMS (ESI ⁺ ): 467.30234 [M + H] ⁺

Using the corresponding starting materials and reactants, the following Examples 18-2 to 18-14 were obtained by the same method as in Example 18-1, the method described in Step 4-2, or a method similar thereto. ..

N- [1-[[4- (3-Hydroxypropyl) phenyl] methylamino] -1-oxohexane-2-yl] -3,6,6-trimethyl-4-oxo-5,7 under an argon atmosphere To a solution of -dihydro-1H-indol-2-carboxamide (50.0 mg) in dichloromethane (1.00 mL), add triethylamine (21.7 μL) and methanesulfonyl chloride (9.67 μL) at 0 ° C. Stirred for 1 hour. By purifying the reaction solution by silica gel column chromatography (hexane: ethyl acetate = 3: 1 to 0: 1), 3-[4-[[2-[(3,6,6-trimethyl-4-oxo-) 5,7-Dihydro-1H-indole-2-carbonyl) amino] hexanoylamino] methyl] phenyl] propyl methanesulfonate (50.0 mg) was obtained.
^{1 1} H-NMR (DMSO-D ₆ , 400MHz) δ: 0.84 (3H, t, J = 7.0 Hz), 1.01 (6H, s), 1.21-1.35 (4H, m), 1.57-1.78 (2H, m) , 1.88-1.97 (2H, m), 2.20 (2H, s), 2.46 (3H, s), 2.59-2.66 (4H, m), 3.16 (3H, s), 4.17 (2H, t, J = 6.4 Hz) ), 4.19-4.31 (2H, m), 4.38-4.47 (1H, m), 7.13-7.19 (4H, m), 7.47-7.55 (1H, m), 8.48-8.56 (1H, m), 11.75 (1H) , s).
MS (ESI ⁺ ): 560.3 [M + H] ⁺

Under an argon atmosphere, 3- [4-[[2-[(3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carbonyl) amino] hexanoylamino] methyl] phenyl ] In a solution of propyl methanesulfonate (50.0 mg) and di-tert-butyl iminodicarboxylic acid (58.2 mg) in N, N-dimethylformamide (1.00 mL) at room temperature, potassium carbonate (37. 0 mg) was added, and the mixture was stirred at 50 ° C. for 8 hours. The reaction mixture was added to water, extracted twice with ethyl acetate, and the combined extraction layers were washed in the order of water and saturated brine, dried over anhydrous sodium sulfate, and the insoluble material was removed by filtration. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 to 0: 1) to tert-butyl N-[(2-methylpropan-2-yl) oxy. Carbonyl] -N- [3- [4- [[2-[(3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carbonyl) amino] hexanoylamino] methyl ] Phenyl] propyl] carbamate (46.0 mg) was obtained.
^{1 1} H-NMR (DMSO-D ₆ , 400MHz) δ: 0.79-0.89 (3H, m), 1.01 (6H, s), 1.20-1.31 (6H, m), 1.40 (18H, s), 1.70-1.79 ( 2H, m), 2.20 (2H, s), 2.46 (3H, s), 2.50-2.54 (2H, m), 2.62 (2H, s), 3.40-3.48 (2H, m), 4.16-4.31 (2H, m) m), 4.38-4.48 (1H, m), 7.08-7.18 (4H, m), 7.46 (1H, d, J = 7.9 Hz), 8.52 (1H, t, J = 6.1 Hz), 11.70 (1H, s) ).
MS (ESI ⁺ ): 681.4 [M + H] ⁺

tert-Butyl N-[(2-Methylpropan-2-yl) Oxycarbonyl] -N- [3- [4-[[2-[(3,6,6-trimethyl-4-oxo-5,7-] Dihydro-1H-indole-2-carbonyl) amino] hexanoylamino] methyl] phenyl] propyl] carbamate (40.0 mg) in a solution of trifluoroacetic acid (0.250 mL) in dichloromethane (0.250 mL) at room temperature. mL) was added and stirred for 2 hours. After distilling off the solvent of the reaction solution under reduced pressure, the residue was purified by aminoated silica gel column chromatography (ethyl acetate: methanol = 1: 0 to 4: 1) to N- [1-[[4- (3). -Aminopropyl) phenyl] methylamino] -1-oxohexane-2-yl] -3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxamide (29.0 mg) ) Was obtained.
^{1 1} H-NMR (DMSO-D ₆ , 400MHz) δ: 0.83-0.91 (3H, m), 1.04 (6H, s), 1.23-1.37 (4H, m), 1.56-1.83 (4H, m), 2.24 ( 2H, s), 2.49 (3H, s), 2.53-2.60 (4H, m), 2.66 (2H, s), 4.20-4.34 (2H, m), 4.42-4.50 (1H, m), 7.12-7.20 ( 4H, m), 7.52 (1H, d, J = 7.9 Hz), 8.54 (1H, t, J = 5.8 Hz).
HRMS (ESI ⁺ ): 481.31785 [M + H] ⁺

Under an argon atmosphere, methyl 4- [2-[(3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carbonyl) amino] hexanoylamino] benzoate (134 mg) Lithium hydroxide monohydrate (60.0 mg) was added to a mixed solution of tetrahydrofuran-methanol-water (1.43 mL, 3: 3: 1), and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure and neutralized with 1 mol / L hydrochloric acid. The resulting solid was collected by filtration and 4- [2-[(3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carbonyl) amino] hexanoylamino] benzoic acid ( 122 mg) was obtained.
¹ H-NMR (DMSO-D ₆ , 400MHz) δ: 0.88 (3H, t, J = 6.7 Hz), 1.02 (6H, s), 1.30-1.44 (4H, m), 1.70-1.84 (2H, m) , 2.23 (2H, s), 2.47 (3H, s), 2.65 (2H, s), 4.56 (1H, td, J = 8.6, 4.9 Hz), 7.68 (1H, d, J = 8.6 Hz), 7.74 ( 2H, d, J = 8.6 Hz), 7.90 (2H, d, J = 8.6 Hz), 10.46 (1H, s), 11.69 (1H, s), 12.71 (1H, s).
HRMS (ESI ⁺ ): 454.23456 [M + H] ⁺

Using the corresponding starting material and reactant, the following Reference Example 82-2 was obtained by the same method as in Reference Example 82-1, the method described in Step 5-1 or a method similar thereto.

4- [2-[(3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carbonyl) amino] hexanoylamino] benzoic acid (50.0 mg) under an argon atmosphere ) N, N-dimethylformamide solution (0.551 mL) with ammonium chloride (29.5 mg), O- (7-azabenzotriazole-1-yl) -N, N, N', N'-tetra Methyluronium hexafluorophosphate (50.2 mg) and N, N-diisopropylethylamine (0.094 mL) were added, and the mixture was stirred at room temperature for 8 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the insoluble matter was removed by filtration. After distilling off the solvent, the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 25% -100% -methanol / ethyl acetate = 20%), and the resulting solid was washed with diisopropyl ether and N- [1- [1- (4-Carbamoylanilino) -1-oxohexane-2-yl] -3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxamide (34.7 mg) Obtained.
¹ H-NMR (DMSO-D ₆ , 400MHz) δ: 0.88 (3H, t, J = 6.7 Hz), 1.03 (6H, s), 1.32-1.42 (4H, m), 1.71-1.82 (2H, m) , 2.23 (2H, s), 2.48 (3H, s), 2.65 (2H, s), 4.57 (1H, td, J = 8.6, 4.9 Hz), 7.25 (1H, br s), 7.67 (2H, d, J = 8.6 Hz), 7.84 (2H, d, J = 8.6 Hz), 7.95 (2H, br s), 10.36 (1H, s), 11.69 (1H, s).
HRMS (ESI ⁺ ): 453.24986 [M + H] ⁺

Using the corresponding starting material and reactant, the following Example 20-2 was obtained by the same method as in Example 20-1, the method described in Step 5-2, or a method similar thereto.

Under an argon atmosphere, 3,6,6-trimethyl-N- [1- (4-nitroanilino) -1-oxohexane-2-yl] -4-oxo-5,7-dihydro-1H-indole-2-carboxamide To a mixed solution of (30.0 mg) methanol (0.500 mL) and tetrahydrofuran (0.500 mL), add 10% palladium carbon (3.00 mg) at room temperature, and stir for 2 hours under a hydrogen atmosphere. After that, hydrogen in the reaction vessel was replaced with argon. After filtering the reaction solution with Celite, the solvent of the filtrate is distilled off under reduced pressure to obtain N- [1- (4-aminoanilino) -1-oxohexane-2-yl] -3,6,6. -Trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxamide (27.0 mg) was obtained.
¹ H-NMR (DMSO-D ₆ , 400MHz) δ: 0.88 (3H, t, J = 7.0 Hz), 1.04 (6H, s), 1.24-1.43 (4H, m), 1.62-1.85 (2H, m) , 2.23 (2H, s), 2.49 (3H, s), 2.65 (2H, s), 4.50-4.58 (1H, m), 4.87 (2H, s), 6.51 (2H, d, J = 8.5 Hz), 7.24 (2H, d, J = 8.5 Hz), 7.54 (1H, d, J = 7.9 Hz), 9.71 (1H, s), 11.75 (1H, s).
HRMS (ESI ⁺ ): 425.25574 [M + H] ⁺

(S) -3,6,6-trimethyl-4-oxo-N- (1-oxo-1-((4- (piperazin-1-yl) benzyl) amino) hexane-2-yl) -4,5 , 6,7-Tetrahydro-1H-Indol-2-carboxamide (62 mg), isobutyraldehyde (110 μL), N, N-diisopropylethylamine (72 μL) hydrogenated in dichloromethane (630 μL) solution under ice cooling Sodium triacetoxyboron (51 mg) was added, the temperature was raised to room temperature, and the mixture was stirred overnight. 2 mL of saturated aqueous sodium hydrogen carbonate solution and 1 mL of 2M aqueous potassium carbonate solution were added, and the mixture was extracted twice with dichloromethane. The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (dichloromethane-methanol) and (S) -N- (1-((4- (4-isopropylpiperazin-1-yl) benzyl) amino) -1-oxohexane-2. -Il) -3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide (28.2 mg) was obtained.
¹ H-NMR (399 MHz, CDCl ₃ ) δ: 0.88 (3H, t, J = 7.3 Hz), 0.93 (6H, d, J = 6.4 Hz), 1.09 (6H, s), 1.28-1.40 (4H, s) m), 1.63-1.99 (3H, m), 2.17 (2H, d, J = 7.8 Hz), 2.33 (2H, s), 2.53-2.60 (4H, m), 2.62 (2H, s), 2.66 (3H) , s), 3.18 (4H, t, J = 4.8 Hz), 4.32 (1H, dd, J = 14.6, 5.5 Hz), 4.42 (1H, dd, J = 14.6, 5.7 Hz), 4.55 (1H, q, J = 6.9 Hz), 6.27 (1H, s), 6.57 (1H, d, J = 7.8 Hz), 6.85 (2H, d, J = 8.7 Hz), 7.15 (2H, d, J = 8.7 Hz), 9.35 (1H, s)
MS (ESI ⁺ ): 565.23 [M + H] ⁺

Using the corresponding starting materials and reactants, the following Examples 22-2 to 22-5 were obtained by the same method as in Example 22-1, the method described in Step 7-1 or a method similar thereto. ..

(S) -3,6,6-trimethyl-4-oxo-N- (1-oxo-1-((4- (piperazin-1-yl) benzyl) amino) hexane-2-yl) -4,5 , 6,7-Tetrahydro-1H-Indol-2-carboxamide (187 mg), 2- (benzyloxy) acetaldehyde (68 mg), N, N-diisopropylethylamine (10.5 μL) dichloromethane (1.5 mL) ) Sodium hydrogenated triacetoxyboron (153 mg) was added to the solution under ice-cooling, the temperature was raised to room temperature, and the mixture was stirred overnight. Saturated aqueous sodium hydrogen carbonate solution (2 mL) and 2M aqueous potassium carbonate solution (2 mL) were added, and the mixture was extracted twice with dichloromethane. The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (dichloromethane-methanol) and (S) -N- (1-((4- (4- (2- (benzyloxy) ethyl) piperazin-1-yl) benzyl) amino). ) -1-oxohexane-2-yl) -3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide (177.9 mg) isolated did.
¹ H-NMR (399 MHz, CDCl ₃ ) δ: 0.88 (3H, t, J = 7.2 Hz), 1.09 (6H, s), 1.26-1.38 (4H, m), 1.63-1.80 (1H, m), 1.88-2.00 (1H, m), 2.33 (2H, s), 2.61 (2H, t, J = 5.3 Hz), 2.62 (2H, s), 2.65-2.70 (9H, m), 3.19 (4H, t, J = 5.2 Hz), 3.67 (2H, t, J = 6.4 Hz), 4.31 (1H, dd, J = 14.6, 4.8 Hz), 4.42 (1H, dd, J = 14.6, 4.8 Hz), 4.5-4.56 ( 1H, m), 6.20 (1H, m), 6.55 (1H, d, J = 8.0 Hz), 6.86 (2H, d, J = 8.8 Hz), 7.15 (2H, d, J = 8.8 Hz), 7.35 ( 5H, m), 9.30 (1H brs).
MS (ESI ⁺ ): 642.18 [M + H] ⁺

(S) -N- (1-((4- (4- (2- (benzyloxy) ethyl) piperazin-1-yl) benzyl) amino) -1-oxohexane-2-yl) -3,6, 6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide (154 mg), 50% hydrated 10% palladium carbon (150 mg), trifluoroacetic acid (55 μL) The methanol (40 mL) mixture was stirred at room temperature for 2 days under a hydrogen atmosphere. The reaction mixture was filtered through Celite, concentrated under reduced pressure, and a dichloromethane-saturated aqueous sodium hydrogen carbonate solution was added to the residue to separate the layers. The aqueous layer was extracted twice, and the combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane-methanol) and (S) -N- (1-((4- (4- (2-hydroxyethyl) piperazin-1-yl) benzyl) amino) -1-. Oxohexane-2-yl) -3,6,6-trimethyll-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide (58.3 mg) was obtained.
¹ H-NMR (399 MHz, CDCl ₃ ) δ: 0.88 (3H, t, J = 7.1 Hz), 1.08 (6H, s), 1.29-1.38 (4H, m), 1.73 (1H, td, J = 14.6) , 7.2 Hz), 1.88-2.00 (1H, m), 2.32 (2H, s), 2.61 (2H, t, J = 5.3 Hz), 2.61 (2H, s), 2.65 (3H, s), 2.67 (4H) , t, J = 4.8 Hz), 3.17 (4H, t, J = 5.0 Hz), 3.67 (2H, t, J = 5.3 Hz), 4.31 (1H, dd, J = 14.6, 5.5 Hz), 4.42 (1H) , dd, J = 14.6, 5.5 Hz), 4.56 (1H, dt, J = 6.9, 6.9 Hz), 6.39 (1H, t, J = 5.5 Hz), 6.63 (1H, d, J = 7.8 Hz), 6.85 (2H, d, J = 8.7 Hz), 7.15 (2H, d, J = 8.7 Hz), 9.55 (1H, brs).
MS (ESI ⁺ ): 552.13 [M + H] ⁺

Under an argon atmosphere, tert-butyl N-methyl-N- [2- [5- [2-[(3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carbonyl)) Trifluoroacetic acid (1.41 mL) was added to a dichloromethane solution (1.41 mL) of amino] hexanoylamino] pyridine-2-yl] oxyethyl] carbamate (330 mg), and the mixture was stirred at room temperature for 2 hours. After concentrating the reaction solution, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the insoluble matter was removed by filtration. After distilling off the solvent, 3,6,6-trimethyl-N- [1-[[6- [2- (methylamino) ethoxy] pyridin-3-yl] amino] -1-oxohexane-2-yl]- 4-Oxo-5,7-dihydro-1H-indole-2-carboxamide (210 mg) was obtained.
¹ H-NMR (DMSO-D ₆ , 400 MHz) δ: 0.87 (3H, t, J = 6.7 Hz), 1.01 (6H, s), 1.25-1.42 (4H, m), 1.65-1.81 (2H, m) ), 2.21 (2H, s), 2.30 (3H, s), 2.46 (3H, s), 2.63 (2H, s), 2.77 (2H, t, J = 5.8 Hz), 4.22 (2H, t, J = 5.8 Hz), 4.53 (1H, td, J = 8.6, 5.5 Hz), 6.77 (1H, d, J = 8.6 Hz), 7.74 (1H, brs), 7.90 (1H, dd, J = 8.6, 2.4 Hz) , 8.35 (1H, d, J = 2.4 Hz), 10.20 (1H, s), 11.80 (1H, brs).
HRMS (ESI ⁺ ): 484.29239 [M + H] ⁺

Using the corresponding starting materials and reactants, the following Examples 24-2 to 24-5 were obtained by the same method as in Example 24-1, the method described in Step 8-1, or a method similar thereto. ..

tert-Butyl 5- [2-[(3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carbonyl) amino] hexanoylamino] -3,4-dihydro-1H Trifluoroacetic acid (0.50 mL) was added to a solution of -isoquinolin-2-carboxylate (55.0 mg) in dichloromethane (0.50 mL) at room temperature, and the mixture was stirred for 2 hours. After distilling off the solvent of the reaction solution under reduced pressure, the residue was purified by aminoated silica gel column chromatography (ethyl acetate: methanol = 97: 3 to 4: 1) to result in 3,6,6-trimethyl-4-oxo. -N- [1-oxo-1- (1,2,3,4-tetrahydroisoquinoline-5-ylamino) hexane-2-yl] -5,7-dihydro-1H-indole-2-carboxamide (31.8) mg) was obtained.
¹ H-NMR (DMSO-D ₆ , 400 MHz) δ: 0.96 (3H, t, J = 6.7 Hz), 1.09 (6H, s), 1.30-1.52 (4H, m), 1.74-1.96 (2H, m) ), 2.29 (2H, s), 2.55 (3H, s), 2.58-2.63 (2H, m), 2.71 (2H, s), 2.93-3.03 (2H, m), 3.89 (2H, s), 4.66- 4.74 (1H, m), 6.92 (1H, d, J = 7.3 Hz), 7.14 (1H, t, J = 7.6 Hz), 7.27 (1H, d, J = 7.9 Hz), 7.64 (1H, d, J) = 7.9 Hz), 9.43 (1H, s), 11.78 (1H, s).
HRMS (ESI ⁺ ): 465.2857 [M + H] ⁺

Using the corresponding starting materials and reactants, the following Examples 25-2 to 25-3 were obtained by the same method as in Example 25-1, the method described in Step 9-1, or a method similar thereto. ..

tert-Butyl 3- [5- [2-[(3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carbonyl) amino] hexanoylamino] pyridin-2-yl ] Oxyazetidine-1-carboxylate was used for synthesis in the same manner as in Example 19.
^{1 1} H-NMR (DMSO-D ₆ , 400 MHz) δ: 0.87 (3H, t, J = 7.3 Hz), 1.01 (6H, s), 1.25-1.41 (4H, m), 1.64-1.83 (2H, m) ), 2.21 (2H, s), 2.46 (3H, s), 2.63 (2H, s), 3.44-3.52 (2H, m), 3.68-3.75 (2H, m), 4.50-4.58 (1H, m), 5.22-5.30 (1H, m), 6.80 (1H, d, J = 8.5 Hz), 7.56-7.64 (1H, m), 7.90 (1H, dd, J = 8.5, 3.0 Hz), 8.31 (1H, d, J = 3.0 Hz), 10.16 (1H, s), 11.66 (1H, br s).
HRMS (ESI ⁺ ): 482.27709 [M + H] ⁺

Using the corresponding starting materials and reactants, the following Examples 26-2 to 26-8 were obtained by the same method as in Example 26-1, the method described in Step 10-1, or a method similar thereto. ..

tert-Butyl 7- [5- [2-[(3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carbonyl) amino] hexanoylamino] pyridin-2-yl ] -2,7-Diazaspiro [3.4] Octane-2-carboxylate was used and synthesized in the same manner as in Example 19.
^{1 1} H-NMR (DMSO-D ₆ , 400 MHz) δ: 0.86 (3H, t, J = 6.7 Hz), 1.01 (6H, s), 1.21-1.42 (4H, m), 1.63-1.80 (2H, m) ), 2.03-2.12 (2H, m), 2.21 (2H, s), 2.46 (3H, s), 2.63 (2H, s), 3.32-3.37 (4H, m), 3.39-3.50 (4H, m), 4.48-4.57 (1H, m), 6.39 (1H, d, J = 9.1 Hz), 7.63-7.74 (2H, m), 8.22 (1H, d, J = 2.4 Hz), 9.91 (1H, s).
HRMS (ESI ⁺ ): 521.32408 [M + H] ⁺

tert-Butyl 4- [4-[[4-Cyclopropyl-1-[(6-methoxypyridin-3-yl) amino] -1-oxobutane-2-yl] carbamoyl] phenyl] piperidin-1-carboxylate ( Trifluoroacetic acid (0.500 mL) was added to a solution of 52.0 mg) in dichloromethane (0.500 mL) at room temperature, and the mixture was stirred for 15 minutes. After distilling off the solvent of the reaction solution under reduced pressure, diisopropylamine (0.100 mL) was added to a solution of the residue in tetrahydrofuran (0.500 mL) at room temperature, and the mixture was stirred for 15 minutes. After distilling off the solvent under reduced pressure, the residue was purified by aminoated silica gel column chromatography (ethyl acetate: methanol = 1: 0 to 9: 1) to obtain N- [4-cyclopropyl-1-[(6-methoxy). Pyridine-3-yl) amino] -1-oxobutane-2-yl] -4-piperidin-4-ylbenzamide (39.0 mg) was obtained.
¹ H-NMR (DMSO-D ₆ , 400 MHz) δ: -0.05-0.08 (2H, m), 0.32-0.43 (2H, m), 0.64-0.76 (1H, m), 1.19-1.38 (2H, m) ), 1.50 (2H, ddd, J = 24.5, 12.2, 3.7 Hz), 1.62-1.72 (2H, m), 1.84-1.95 (2H, m), 2.52-2.68 (3H, m), 2.96-3.06 (2H) , m), 3.80 (3H, s), 4.56 (1H, q, J = 7.9 Hz), 6.78 (1H, d, J = 8.6 Hz), 7.30 (2H, d, J = 8.6 Hz), 7.84 (2H) , d, J = 8.6 Hz), 7.90 (1H, dd, J = 8.6, 2.4 Hz), 8.36 (1H, d, J = 2.4 Hz), 8.48 (1H, d, J = 7.9 Hz), 10.09 (1H) , s).
HRMS (ESI ⁺ ): 437.25501 [M + H] ⁺

Same as Reference Example 5 using N- [6- (1-methylpiperidin-4-yl) oxypyridin-3-yl] -2-[[2- (2-nitrophenyl) acetyl] amino] hexaneamide. Synthesized into.
¹ H-NMR (DMSO-D ₆ , 400 MHz) δ: 0.82 (3H, t, J = 7.0 Hz), 1.17-1.33 (4H, m), 1.52-1.75 (4H, m), 1.88-1.97 (2H) , m), 2.12-2.24 (5H, m), 2.58-2.70 (2H, m), 3.32-3.35 (1H, m), 3.38 (1H, d, J = 13.9 Hz), 4.30-4.40 (1H, m) ), 4.85-4.94 (1H, m), 5.04 (2H, s), 6.49 (1H, td, J = 7.3, 1.2 Hz), 6.62 (1H, d, J = 7.3 Hz), 6.73 (1H, d, J = 9.1 Hz), 6.91 (1H, td, J = 7.6, 1.2 Hz), 7.00 (1H, dd, J = 7.6, 1.2 Hz), 7.86 (1H, dd, J = 9.1, 2.4 Hz), 8.30 ( 1H, d, J = 2.4 Hz), 8.35 (1H, d, J = 7.9 Hz), 10.05 (1H, s).
HRMS (ESI ⁺ ): 454.28121 [M + H] ⁺

In an argon atmosphere, 2-cyclopropyl-2-[(2-methylpropan-2-yl) oxycarbonylamino] butanoic acid (100 mg) in an N, N-dimethylformamide solution (2.06 mL). N-Methylbenzene-1,2-diamine (0.047 mL), 1-hydroxybenzotriazole monohydrate (75.5 mg), N, N-diisopropylethylamine (0.105 mL), 1-ethyl- 3- (3-Dimethylaminopropyl) carbodiimide hydrochloride (86.6 mg) was added, and the mixture was stirred at room temperature for 22 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the insoluble matter was removed by filtration. After distilling off the solvent, acetic acid (1.37 mL) was added, and the mixture was stirred at 60 ° C. for 4 hours. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the insoluble matter was removed by filtration. After distilling off the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) and tert-butyl N- [3-cyclopropyl-1- (1-methylbenzoimidazole-2-yl)). Propyl] carbamate (96.1 mg) was obtained.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: -0.03-0.06 (2H, m), 0.40-0.43 (2H, m), 0.67-0.75 (1H, m), 1.20-1.33 (2H, m), 1.43 (9H, s), 2.01-2.19 (2H, m), 3.83 (3H, s), 5.11 (1H, td, J = 7.9, 6.1 Hz), 5.29 (1H, d, J = 8.6 Hz), 7.24 -7.31 (2H, m), 7.32-7.36 (1H, m), 7.73 (1H, dd, J = 7.3, 1.8 Hz).
HRMS (ESI ⁺ ): 330.21755 [M + H] ⁺

Using the corresponding starting materials and reactants, the following Reference Examples 84-2 to 84-6 were obtained by the same method as in Reference Example 84-1, the method described in Step 39-1, or a method similar thereto. ..

Trifluoro in a dichloromethane solution (0.729 mL) of tert-butyl N- [3-cyclopropyl-1- (1-methylbenzoimidazole-2-yl) propyl] carbamate (96.1 mg) under an argon atmosphere. After adding acetic acid (0.729 mL) and stirring at room temperature for 30 minutes, the reaction solution was concentrated under reduced pressure. 3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indol-2-carboxylic acid (64.6 mL) in an N, N-dimethylformamide solution (1.46 mL) of the obtained crude product. 6 mg), 1-hydroxybenzotriazole monohydrate (53.6 mg), N, N-diisopropylethylamine (0.199 mL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride ( 61.5 mg) was added, and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the insoluble matter was removed by filtration. After distilling off the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1), and the resulting solid was washed with diisopropyl ether and N- [3-cyclopropyl-1- (1-methylbenzo). Imidazole-2-yl) propyl] -3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxamide (92.8 mg) was obtained.
¹ H-NMR (DMSO-D ₆ , 400MHz) δ: 0.00-0.10 (2H, m), 0.43 (2H, dd, J = 7.9, 1.8 Hz), 0.74-0.82 (1H, m), 1.04 (6H, m) s), 1.26-1.37 (2H, m), 2.11-2.21 (2H, m), 2.24 (2H, s), 2.48 (3H, s), 2.65 (2H, s), 3.85 (3H, s), 5.50 (1H, td, J = 8.6, 6.1 Hz), 7.22 (1H, ddd, J = 8.6, 7.3, 1.2 Hz), 7.27 (1H, ddd, J = 8.6, 7.3, 1.2 Hz), 7.56 (1H, dd) , J = 7.3, 1.2 Hz), 7.63 (1H, dd, J = 7.3, 1.2 Hz), 8.05 (1H, d, J = 8.6 Hz), 11.61 (1H, s).
HRMS (ESI ⁺ ): 433.25981 [M + H] ⁺

Using the corresponding starting materials and reactants, the following Examples 30-2 to 30 can be carried out by the same method as in Example 30-1, the method described in Steps 39-2 to 39-3, or a method similar thereto. I got -4.

3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid (604 mg), (S) -1- (6- (benzyloxy) -1H -Benz [d] imidazol-2-yl) pentan-1-amine (845 mg) in tetrahydrofuran (10 mL) solution with 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-Methylmorpholinium chloride (906.5 mg) was added under ice-cooling. The mixed solution was returned to room temperature and stirred overnight. Ethyl acetate, water, and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution to carry out a liquid separation operation, and the organic layer was separated. The aqueous layer was re-extracted once with ethyl acetate. The combined organic layers were washed with saturated brine-sodium hydrogen carbonate aqueous solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel lucagel column chromatography (ethyl acetate-hexane), crystallized while concentrating from chloroform, washed with heptane, and (S) -N- (1- (6- (benzyloxy) -1H-benz). [D] Imidazole-2-yl) pentyl) -3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide (990 mg) was isolated.
¹ H-NMR (399 MHz, CDCl ₃ ) δ: 0.83 (3H, t, J = 7.0 Hz), 0.99 (6H, s), 1.23-1.39 (4H, m), 1.83-1.95 (1H, m), 1.98-2.11 (1H, m), 2.19 (2H, s), 2.48 (3H, s), 261 (2H, s), 5.09 (2H, s), 5.19 (1H, q, J = 6.0 Hz), 6.85 (1H, m), 7.01 (0.6H, s), 7.17 (0.4H, s), 7.29 (1H, d, J = 7.2 Hz), 7.36 (3H, m), 7.43 (2H, d, J = 7.2) Hz), 7.80 (1H, d, J = 8.4 Hz), 11.59 (1H, s), 12.12 (1H, m).
MS (ESI ⁺ ): 513.14 [M + H] ⁺

Under an argon atmosphere, in a carbon tetrachloride solution (5.82 mL) of tert-butyl N- [3-cyclopropyl-1- (1,7-dimethylbenzoimidazol-2-yl) propyl] carbamate (200 mg). N-Bromosuccinimide (104 mg) and 2,2′-azobis (isobutyronitrile) (4.8 mg) were added at room temperature, and the mixture was stirred at 80 ° C. for 5 hours. A saturated aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the insoluble matter was removed by filtration. After distilling off the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) and tert-butyl N- [1- [7- (bromomethyl) -1-methylbenzoimidazole-2-yl). ] -3-Cyclopropylpropyl] Carbamate (149 mg) was obtained.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: -0.01-0.09 (2H, m), 0.42-0.47 (2H, m), 0.69-0.77 (1H, m), 1.25-1.36 (2H, m), 1.45 (9H, s), 2.13-2.20 (2H, m), 4.26 (3H, s), 4.87 (1H, d, J = 10.9 Hz), 4.93 (1H, d, J = 10.9 Hz), 5.15-5.23 (1H, m), 7.24-7.27 (2H, m), 7.77 (1H, t, J = 4.8 Hz).
HRMS (ESI ⁺ ): 422.14443 [M + H] ⁺

Using the corresponding starting materials and reactants, the following Reference Examples 86-2 to 86-3 were obtained by the same method as in Reference Example 86-1, the method described in Step 40-1, or a method similar thereto. ..

Under an argon atmosphere, a solution of tert-butyl N- [1- [7- (bromomethyl) -1-methylbenzoimidazole-2-yl] -3-cyclopropylpropyl] carbamate (149 mg) in tetrahydrofuran (1.76 mL). ) Was added with dimethylamine (0.353 mL, 2 mol / L tetrahydrofuran solution) at room temperature, and the mixture was stirred at room temperature for 4 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the insoluble matter was removed by filtration. After distilling off the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) and tert-butyl N- [3-cyclopropyl-1- [7-[(dimethylamino) methyl] -1). -Methylbenzoimidazole-2-yl] propyl] carbamate (100 mg) was obtained.
HRMS (ESI ⁺ ): 387.27547 [M + H] ⁺

Using the corresponding starting materials and reactants, the following Reference Examples 87-2 to 87-7 were obtained by the same method as in Reference Example 87-1, the method described in Step 40-2, or a method similar thereto. ..

Under an argon atmosphere, a dichloromethane solution of tert-butyl N- [3-cyclopropyl-1- [7-[(dimethylamino) methyl] -1-methylbenzoimidazol-2-yl] propyl] carbamate (100 mg) ( Trifluoroacetic acid (0.647 mL) was added to 0.647 mL), and the mixture was stirred at room temperature for 30 minutes, and then the reaction solution was concentrated under reduced pressure. In the obtained crude product N, N-dimethylformamide solution (1.29 mL), 3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indol-2-carboxylic acid (57. 3 mg), 1-hydroxybenzotriazole monohydrate (47.5 mg), N, N-diisopropylethylamine (0.175 mL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (3 mg) 54.6 mg) was added, and the mixture was stirred at room temperature for 8 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the insoluble matter was removed by filtration. After distilling off the solvent, the residue was purified by aminoated silica gel column chromatography (hexane: ethyl acetate = 1: 1), and the resulting solid was washed with diisopropyl ether and N- [3-cyclopropyl-1- [7-]. [(Dimethylamino) methyl] -1-methylbenzoimidazole-2-yl] propyl] -3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxamide (73. 6 mg) was obtained.
¹ H-NMR (DMSO-D ₆ , 400 MHz) δ: 0.00-0.11 (2H, m), 0.42-0.46 (2H, m), 0.75-0.83 (1H, m), 1.05 (6H, s), 1.28 -1.39 (2H, m), 2.09-2.15 (2H, m), 2.19 (6H, s), 2.25 (2H, s), 2.50 (3H, s), 2.66 (2H, s), 3.64 (1H, d) , J = 12.7 Hz), 3.75 (1H, d, J = 12.7 Hz), 4.15 (3H, s), 5.53 (1H, td, J = 8.5, 5.4 Hz), 7.03 (1H, d, J = 7.9 Hz) ), 7.13 (1H, t, J = 7.9 Hz), 7.58 (1H, dd, J = 7.9, 1.2 Hz), 8.05 (1H, d, J = 8.5 Hz), 11.62 (1H, s).
HRMS (ESI ⁺ ): 490.31795 [M + H] ⁺

Using the corresponding starting materials and reactants, the following Examples 31-2 to 31 can be carried out by the same method as in Example 31-1, the method described in Steps 39-2 to 39-3 or a method similar thereto. I got -7.

Under an argon atmosphere, methyl 2- [3-cyclopropyl-1-[(2-methylpropan-2-yl) in a tetrahydrofuran solution (3.00 mL) of lithium aluminum hydride (49.0 mg) under ice-cooling. Oxycarbonylamino] propyl] -1-methylbenzimidazole-5-carboxylate (418 mg) in tetrahydrofuran (2.39 mL) was added and stirred at room temperature for 2 hours. Water (0.050 mL), 15% aqueous sodium hydroxide solution (0.050 mL), and water (0.150 mL) were added to the reaction mixture, and the mixture was filtered through Celite. After distilling off the solvent, the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 50%) and tert-butyl N- [3-cyclopropyl-1- [5- (hydroxymethyl) -1-methylbenzoimidazole). Lu-2-yl] propyl] carbamate (224 mg) was obtained.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 0.00-0.08 (2H, m), 0.42-0.47 (2H, m), 0.65-0.73 (1H, m), 1.26-1.35 (2H, m), 1.38 (9H, s), 2.17-2.28 (1H, m), 2.47-2.57 (1H, m), 4.07 (3H, s), 4.84 (2H, s), 5.23-5.28 (1H, m), 7.51 (1H) , d, J = 8.5 Hz), 7.58 (1H, dd, J = 8.5, 1.2 Hz), 7.93 (1H, d, J = 1.2 Hz).
HRMS (ESI ⁺ ): 360.22903 [M + H] ⁺

Under an argon atmosphere, a dichloromethane solution (2.06) of tert-butyl N- [3-cyclopropyl-1- [5- (hydroxymethyl) -1-methylbenzoimidazole-2-yl] propyl] carbamate (148 mg). To (mL) was added triphenylphosphine (130 mg) and carbon tetrabromide (191 mg) at room temperature, and the mixture was stirred at room temperature for 4 hours. After concentrating the reaction solution under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) and tert-butyl N- [1- [5- (bromomethyl) -1-methylbenzoimidazole). Lu-2-yl] -3-cyclopropylpropyl] carbamate (118 mg) was obtained.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 0.01-0.07 (2H, m), 0.43-0.48 (2H, m), 0.66-0.72 (1H, m), 1.25-1.34 (2H, m), 1.38 (9H, s), 2.18-2.28 (1H, m), 2.49-2.59 (1H, m), 4.08 (3H, s), 4.59 (2H, s), 5.25 (1H, brs), 7.52 (1H, d) , J = 8.5 Hz), 7.60 (1H, d, J = 8.5 Hz), 8.02 (1H, s).
MS (ESI ⁺ ): 422.2 [M + H] ⁺

Under an argon atmosphere, a solution of tert-butyl N- [1- [5- (bromomethyl) -1-methylbenzoimidazole-2-yl] -3-cyclopropylpropyl] carbamate (118 mg) in tetrahydrofuran (1.40 mL) ) Was added with dimethylamine (0.279 mL, 2 mol / L tetrahydrofuran solution) at room temperature, and the mixture was stirred at room temperature for 7 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the insoluble matter was removed by filtration. After distilling off the solvent, the residue was purified by amination silica gel column chromatography (hexane: ethyl acetate = 1: 1) and tert-butyl N- [3-cyclopropyl-1- [5-[(dimethylamino) methyl]. -1-Methylbenzoimidazole-2-yl] propyl] carbamate (98.4 mg) was obtained.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 0.00-0.06 (2H, m), 0.40-0.44 (2H, m), 0.70-0.77 (1H, m), 1.25-1.29 (2H, m), 1.40 (9H, s), 1.96-2.06 (2H, m), 2.16 (6H, s), 3.49 (2H, s), 3.80 (3H, s), 4.94 (1H, td, J = 8.5, 6.1 Hz), 7.20 (1H, dd, J = 8.5, 1.2 Hz), 7.42-7.47 (2H, m).
HRMS (ESI ⁺ ): 387.27542 [M + H] ⁺

Dichloromethane of tert-butyl N- [3-cyclopropyl-1- [5-[(dimethylamino) methyl] -1-methylbenzoimidazol-2-yl] propyl] carbamate (98.4 mg) under an argon atmosphere. Trifluoroacetic acid (0.636 mL) was added to the solution (0.636 mL), and the mixture was stirred at room temperature for 30 minutes, and then the reaction mixture was concentrated under reduced pressure. In the obtained crude product N, N-dimethylformamide solution (1.27 mL), 3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indol-2-carboxylic acid (56. 4 mg), 1-hydroxybenzotriazole monohydrate (46.7 mg), N, N-diisopropylethylamine (0.173 mL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (4 mg) 53.7 mg) was added, and the mixture was stirred at room temperature for 7 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the insoluble matter was removed by filtration. After distilling off the solvent, the residue was purified by aminoated silica gel column chromatography (methanol: ethyl acetate = 1: 9), and the resulting solid was washed with diisopropyl ether and N- [3-cyclopropyl-1- [5-]. [(Dimethylamino) methyl] -1-methylbenzoimidazole-2-yl] propyl] -3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxamide (81. 5 mg) was obtained.
^{1 1} H-NMR (DMSO-D ₆ , 400MHz) δ: -0.01-0.10 (2H, m), 0.43 (2H, dd, J = 8.5, 1.8 Hz), 0.72-0.83 (1H, m), 1.03 (3H) , S), 1.04 (3H, s), 1.24-1.39 (2H, m), 2.03-2.15 (2H, m), 2.16 (6H, s), 2.24 (2H, s), 2.48 (3H, s), 2.64 (2H, s), 3.49 (2H, s), 3.83 (3H, s), 5.43-5.51 (1H, m), 7.21 (1H, dd, J = 8.5, 1.8 Hz), 7.46-7.51 (2H, s) m), 8.07 (1H, d, J = 8.5 Hz), 11.67 (1H, brs).
HRMS (ESI ⁺ ): 490.31747 [M + H] ⁺

Under an argon atmosphere, a solution of tert-butyl N- [3-cyclopropyl-1- [5- (hydroxymethyl) -1-methylbenzoimidazole-2-yl] propyl] carbamate (70.0 mg) in dichloromethane (0) Trifluoroacetic acid (0.487 mL) was added to .487 mL), and the mixture was stirred at room temperature for 30 minutes, and then the reaction solution was concentrated under reduced pressure. In the obtained crude product N, N-dimethylformamide solution (0.974 mL), 3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indol-2-carboxylic acid (43. 1 mg), 1-hydroxybenzotriazole monohydrate (35.8 mg), N, N-diisopropylethylamine (0.132 mL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1 mg) 41.0 mg) was added, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the insoluble matter was removed by filtration. After distilling off the solvent, the residue was purified by silica gel column chromatography (ethyl acetate), and the resulting solid was washed with diisopropyl ether to N- [3-cyclopropyl-1- [5- (hydroxymethyl) -1-methyl). Benzoimidazole-2-yl] propyl] -3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxamide (40.8 mg) was obtained.
¹ H-NMR (DMSO-D ₆ , 400MHz) δ: -0.01-0.09 (2H, m), 0.43 (2H, dd, J = 7.9, 2.4 Hz), 0.73-0.81 (1H, m), 1.04 (6H) , S), 1.27-1.35 (2H, m), 2.08-2.22 (2H, m), 2.24 (2H, s), 2.47 (3H, s), 2.65 (2H, s), 3.84 (3H, s), 4.61 (2H, d, J = 5.4 Hz), 5.16 (1H, t, J = 5.4 Hz), 5.48 (1H, td, J = 8.5, 6.1 Hz), 7.24 (1H, d, J = 8.5 Hz), 7.49 (1H, d, J = 8.5 Hz), 7.56 (1H, s), 8.06 (1H, d, J = 8.5 Hz), 11.61 (1H, s).
HRMS (ESI ⁺ ): 463.27046 [M + H] ⁺

(S) -N- (1- (6- (benzyloxy) -1H-benzo [d] imidazol-2-yl) pentyl) -3,6,6-trimethyl-4-oxo-4,5,6 7-Tetrahydro-1H-indole-2-carboxamide (100 mg) in dichloromethane (1.3 mL solution), 1.01 M di-tert-butyl dicarbonate in ethyl acetate solution (441 μL), 4-dimethylaminopyridine ( 25 mg) was added under ice-cooling and stirred for 1 hour. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate-heptane) (S) -6- (benzyloxy) -2-. (1- (1- (tert-butoxycarbonyl) -3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide) pentyl) -1H-benzo [ d] Imidazole-1-carboxylate tert-butyl (141 mg) was obtained.
(S) -6- (benzyloxy) -2-(1-(1- (tert-butoxycarbonyl) -3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- Indole-2-carboxamide) pentyl) -1H-benzo [d] imidazole-1-carbonate tert-butyl (147 mg), 50% water-containing 10% palladium carbon (44.7 mg) in methanol (5 mL). , Stirred in a hydrogen atmosphere for 2 hours. The reaction mixture was filtered through Celite, concentrated under reduced pressure, and azeotroped with acetone to (S) -2-(1- (1- (tert-butoxycarbonyl) -3,6,6-trimethyl-4-oxo-4,5,6). , 7-Tetrahydro-1H-indole-2-carboxamide) pentyl) -6-hydroxy-1H-benzo [d] imidazol-1-carbonate tert-butyl (127 mg) was obtained.
MS (ESI ⁺ ): 623.19 [M + H] ⁺

(S) -2- (1- (1- (tert-butoxycarbonyl) -3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide) pentyl ) -6-Hydroxy-1H-benzo [d] imidazole-1-carbonate tert-butyl (125 mg) in toluene (1 mL solution, triphenylphosphine (131 mg), 3- (dimethylamino) propan-1- All (51.6 mg) and diisopropyl azodicarboxylate (97 μL) were added under ice-salt cooling, then returned to room temperature and stirred overnight. The reaction was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography (Toluene- Purified with (methanol) and (S) -2-(1-(1- (tert-butoxycarbonyl) -3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol) -2-Carboxamide) Pentyl) -6- (3- (dimethylamino) propyloxy) -1H-benzo [d] imidazole-1-carbonate tert-butyl (81.6 mg) was obtained.
(S) -2- (1- (1- (tert-butoxycarbonyl) -3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide) pentyl ) -6- (3- (Dimethylamino) propyloxy) -1H-benzo [d] imidazole-1-butyl carbonate (81.6 mg) in dichloromethane (3.7 mL) and trifluoroacetic acid (1. 8 mL) was added, and the mixture was stirred overnight at room temperature. It was concentrated under reduced pressure and azeotroped with dichloromethane. The residue was purified by silica gel column chromatography (dioxide-methanol) and (S) -N- (1- (6- (3- (dimethylamino) propyloxy) -1H-benzo [d] imidazol-2-yl). Pentyl) -3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide (57.2 mg) was obtained.
¹ H-NMR (400 MHz, DMSO-D ₆ ) δ: 0.87 (3H, t, J = 6.6 Hz), 1.02 (6H, s), 1.26-1.38 (4H, m), 1.78-1.96 (3H, m) ), 1.98-2.13 (1H, m), 2.16 (6H, s), 2.23 (2H, s), 2.38 (2H, t, J = 7.1 Hz), 2.49 (3H, s), 2.65 (2H, s) , 3.99 (2H, t, J = 6.4 Hz), 5.22 (1H, dd, J = 13.7, 7.8 Hz), 6.75 (1H, dd, J = 8.7, 2.3 Hz), 6.93 (0.6H, d, J = 2.3 Hz), 7.07 (0.4H, d, J = 2.3 Hz), 7.30 (0.4H, d, J = 8.7 Hz), 7.42 (0.6H, d, J = 8.7 Hz), 7.86 (1H, d, J) = 8.2 Hz), 11.64 (1H, s), 12.10 (0.6H, brs), 12.15 (0.4H, brs).
MS (ESI ⁺ ): 508.15 [M + H] ⁺

Using the corresponding starting material and reactant, the following Examples 34-2 to 34 were carried out by the same method as in Example 34-1 and the method described in Steps 42-3 to 42-4 or a method similar thereto. I got -4.

(S) -2- (1- (1- (tert-butoxycarbonyl) -3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide) pentyl ) -6-Hydroxy-1H-benzo [d] imidazol-1-carboxylate-butyl (249 mg) in toluene (2.1 mL) with triphenylphosphine (262 mg), 4-hydroxypiperidine-1- Benzyl carboxylate (235 mg) and diisopropyl azodicarboxylate (194 μL) were added under ice-salt cooling, then returned to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane-methanol). 1- (1- (tert-butoxycarbonyl) -3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide) pentyl) -1H-benzo [d ] Imidazole-1-carbonate tert-butyl carbonate (489 mg) was obtained.
(S) -6-((1-((benzyloxy) carbonyl) piperidine-4-yl) oxy) -2-(1-(1- (tert-butoxycarbonyl) -3,6,6-trimethyl-4) -Oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide) pentyl) -1H-benzo [d] imidazole-1-carbonate tert-butyl (489 mg) in dichloromethane solution (38 μL) Trifluoroacetic acid (45 μL) was added and stirred overnight at room temperature. It was concentrated under reduced pressure and azeotroped with dichloromethane. The residue was purified by silica gel column chromatography (dichloromethane-methanol) and (S) -3,6,6-trimethyl-4-oxo-N- (1- (6-piperidin-4-yloxy) -1H-benzo [ d] Imidazole-2-yl) pentyl) -4,5,6,7-tetrahydro-1H-indole-2-carboxamide (127 mg) was obtained.
^{1 1} H-NMR (399 MHz, DMSO-D ₆ ) δ: 0.87 (3H, t, J = 6.9 Hz), 1.02 (6H, s), 1.22-1.40 (4H, m), 1.45-1.65 (2H, m) ), 1.80-2.10 (4H, m), 2.22 (2H, s), 2.49 (3H, s), 2.55-2.82 (2H, m), 2.65 (2H, s), 2.95-3.09 (2H, m), 3.35 (1H, brs), 4.21-4.47 (1H, m), 5.21 (1H, dd, J = 15.3, 7.1 Hz), 6.79 (1H, d, J = 6.9 Hz), 6.97 (0.6H, brs), 7.14 (0.4H, brs), 7.32 (0.4H, brs), 7.42 (0.6H, brs), 7.86 (1H, d, J = 7.8 Hz), 11.63 (1H, s), 12.10 (0.6H, brs) , 12.16 (0.4H, brs).
MS (ESI ⁺ ): 506.22 [M + H] ⁺

Using the corresponding starting material and reactant, the following Example 35-2 is obtained by the same method as in Example 35-1, the method described in Steps 43-1 to 43-3, or a method similar thereto. It was.

(S) -2- (1- (1- (tert-butoxycarbonyl) -3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide) pentyl ) -6-Hydroxy-1H-benzo [d] imidazol-1-carboxylate (249 mg) in a toluene (2.13 mL) solution of triphenylphosphine (262 mg), 2-((t-butyl). Didimethylsilyl) oxy) ethanol (176 mg) and diisopropyl azodicarboxylate (194 μL) were added under ice-salt cooling, then returned to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane-methanol). Oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide) pentyl) -6-(2-((tert-butyldimethylsilyl) oxy) ethoxy) -1H-benzo [d] imidazole-1 -Tert-Butyl carbonate (260 mg) was obtained.
(S) -2- (1- (1- (tert-butoxycarbonyl) -3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide) pentyl ) -6-(2-((tert-Butyldimethylsilyl) oxy) ethoxy) -1H-benzo [d] imidazol-1-carbonate tert-butyl (260 mg) in dichloromethane (2.14 mL). Fluoroacetic acid (12.8 mL) was added and stirred overnight at room temperature. It was concentrated under reduced pressure and azeotroped twice with dichloromethane. The residue was purified by silica gel column chromatography (dioxide-methanol-ammonia) and (S) -N- (1- (6- (2-hydroxyethoxy) -1H-benzo [d] imidazol-2-yl) pentyl). -3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide (49.5 mg) was obtained.
¹ H-NMR (399 MHz, DMSO-D ₆ ) δ: 0.87 (3H, t, J = 6.9 Hz), 1.03 (6H, s), 1.25-1.41 (4H, m), 1.85-2.14 (2H, m) ), 2.23 (2H, s), 2.49 (3H, s), 2.65 (2H, s), 3.34 (1H, brs), 3.73 (2H, t, J = 5.0 Hz), 3.99 (2H, t, J = 5.0 Hz), 4.87 (1H, brs), 5.23 (1H, dd, J = 14.2, 8.2 Hz), 6.84 (1H, dd, J = 8.7, 1.8 Hz), 7.04 (1H, d, J = 1.8 Hz) , 7.43 (1H, d, J = 8.7 Hz), 7.90 (1H, d, J = 7.8 Hz), 11.65 (1H, s).
MS (ESI ⁺ ): 467.18 [M + H] ⁺

(S) -2- (1- (1- (tert-butoxycarbonyl) -3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide) pentyl ) -6-Hydroxy-1H-benzo [d] imidazol-1-carbonate tert-butyl (31.1 mg) in a toluene (230 μL) solution with triphenylphosphine (26.2 mg), 2-bromoethanol ( 9.4 mg) and diisopropyl azodicarboxylate (20.2 μL) were added under ice-salt cooling, and then the temperature was returned to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane-methanol). , 6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-carboxamide) pentyl) -1H-benzo [d] imidazole-1-carbonate tert-butyl (48.4) mg) was obtained.
MS (ESI ⁺ ): 729.06 [M + H] ⁺

(S) -6- (2-Bromoethoxy) -2-(1-(1- (tert-butoxycarbonyl) -3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro- 1H-indole-2-carboxamide) pentyl) -1H-benzo [d] imidazole-1-carbonate tert-butyl (48.4 mg) in dichloromethane (563 μL) solution, trifluoroacetic acid (51. 1 μL) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and azeotroped with dichloromethane. Ethyl acetate and saturated sodium hydrogen carbonate were added, and the organic layer was separated. The aqueous layer was re-extracted twice, and the combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane-methanol) and (S) -N- (1- (6- (2-bromoethoxy) -1H-benzo [d] imidazol-2-yl) pentyl) -3. , 6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide (37.5 mg) was obtained.
MS (ESI ⁺ ): 529.00 [M + H] ⁺

(S) -N- (1- (6- (2-Bromoethoxy) -1H-benzo [d] imidazol-2-yl) pentyl) -3,6,6-trimethyl-4-oxo-4,5 Piperidine (25.5 mg) was added to a solution of 6,7-tetrahydro-1H-indole-2-carboxamide (53 mg) in acetonitrile (2 mL), and the mixture was stirred at 50 ° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane-methanol). Piperidine-1-yl) ethoxy) -1H-benzo [d] imidazol-2-yl) pentyl) -4,5,6,7-tetrahydro-1H-indole-2-carboxamide (17.5 mg) was obtained. ..
^{1 1} H-NMR (500 MHz, DMSO-D ₆ ) δ: 0.87 (3H, s), 1.03 (6H, s), 1.12-1.43 (6H, m), 1.45- 1.58 (4H, m), 1.84-1.97 (1H, m), 1.97-2.15 (1H, m), 2.23 (2H, s), 2.45 (3H, s), 2.51 (4H, m), 2.66 (4H, m), 4.06 (2H, m), 5.23 (1H, m), 6.77 (1H, m), 6.95 (0.6H, m), 7.10 (0.4H, m), 7.32 (0.4H, m), 7.43 (0.6H, m), 7.87 (1H, m) m), 11.65 (1H, s), 12.12 (1H, s).
MS (ESI ⁺ ): 534.13 [M + H] ⁺

Using the corresponding starting materials and reactants, the following Examples 37-2 to 37-4 were obtained by the same method as in Example 37-1, the method described in Step 45-3, or a method similar thereto. ..

Synthesis of benzyl 4-hydroxyindolin-1-carboxylate A solution of 4-hydroxyindole (5.32 g) in acetic acid (100 mL) is ice-cooled and sodium cyanoborohydride (7.54 g) at 15 ° C to 20 ° C. ) Was added in portions over about 30 minutes. The ice bath was removed, the mixture was stirred at room temperature for 1 hour, and the mixture was concentrated under reduced pressure. The mixture was azeotroped with a mixed solution of methanol, ethanol and toluene, and the residue was diluted with saturated aqueous sodium hydrogen carbonate (150 mL) and tetrahydrofuran (30 mL). A solution of benzyl chloroformate (5.64 g) in ethyl acetate (5 mL) was added thereto under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The organic layer was separated and washed with saturated brine. Benzyl4-hydroxyindrin-1-carboxylate of 7.16 g (66.5%) was obtained by washing the solid precipitated from the concentrated residue with ethyl acetate / hexane (1/9) after drying over sodium sulfate. Was obtained.
^{1 1} H-NMR (CDCl ₃ , 400 MHz) δ: 3.05 (2H, t, J = 8.6 Hz), 4.09 (2H, t, J = 8.6 Hz), 5.09 (1H, s), 5.26 (2H, s) , 6.44 (1H, d, J = 8.4 Hz), 7.05 (1H, br. S), 7.33-7.55 (6H, m).
^{MS (ESI +): 270 [} M + H] +; (ESI -): 268 [MH] -

Synthesis of Benzyl4- (2- (Dimethylamino) ethoxy) Indolin-1-carboxylate A solution of benzyl4-hydroxyindolin-1-carboxylate (269 mg) in tetrahydrofuran (5 mL) was ice-cooled and 2- (dimethyl) 2- (dimethyl) Amino) ethanol (267 mg), triphenylphosphine (918 mg) and bis azodicarboxylate (2-methoxyethyl) (703 mg) were added in sequence. After stirring overnight at room temperature, the concentrated residue of the reaction solution was purified by amino silica gel column chromatography (10-50% ethyl acetate-hexane) and 252 mg (74.0%) of benzyl 4- (2- (dimethylamino)). Ethoxy) Indolin-1-carboxylate was obtained.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 2.33 (6H, s), 2.72 (2H, t, J = 6.0 Hz), 3.04 (2H, t, J = 8.0 Hz), 4.05 (2H, t, J = 8.0 Hz), 4.10 (2H, t, J = 6.0 Hz), 5.25 (2H, s), 6.51 (1H, d, J = 8.4 Hz), 7.14 (1H, br. S), 7.32-7.55 ( 6H, m).
MS (ESI ⁺ ): 341.3 [M + H] ⁺

Synthesis of 2- (Indoline-4-yloxy) -N, N-dimethylethane-1-amine Methanol (5 mL) of benzyl4- (2- (dimethylamino) ethoxy) indoline-1-carboxylate (240 mg) The solution was ice-cooled, 20% palladium carbon (40% wet, 100 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 30 minutes. The reaction mixture was filtered through Celite to obtain 2- (indolin-4-yloxy) -N, N-dimethylethane-1-amine as a concentrated residue of the filtrate. This residue was used as it was in the synthesis of the compound of Example 1-122, which is the step of the next condensation reaction.
MS (ESI ⁺ ): 207 [M + H] ⁺

Using the corresponding starting materials and reactants, the following Reference Examples 96-2 to 96-9 were obtained from Reference Example 94 by the same method as in Reference Example 96-1 or a method similar thereto.

Synthesis of benzyl (S)-(4-cyclopropyl-1- (4- (2- (dimethylamino) ethoxy) indolin-1-yl) -1-oxobutane-2-yl) carbamate Benzyl4-hydroxyindrin-1 -A suspension of 20% palladium carbon (40% wet, 106 mg) in methanol (3.0 mL) was added to a solution of carboxylate (408 mg) in methanol (7.0 mL) at room temperature under a hydrogen atmosphere. Stirred for hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give a residue.
The obtained residue was diluted to dimethylformamide (8.0 mL) under a nitrogen stream, and (S) -2-(((benzyloxy) carbonyl) amino) -4-cyclopurpilbutyric acid (277 mg), 1-hydroxy. Benzotriazole monohydrate (230 mg) and diisopropylethylamine (261 μL) were added and ice-cooled. 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (288 mg) was added to this mixed solution, and the mixture was stirred at room temperature for 2.5 hours. Water (30 mL) was added to the reaction solution, the aqueous layer was extracted with ethyl acetate (7 mL × 5), the organic layer was washed with saturated brine (20 mL), and dried over sodium sulfate. The concentrated residue was purified twice by silica gel column chromatography (0-8% methanol- dichloromethane) and amino silica gel chromatography (10-50% ethyl acetate-hexane) and 268 mg (58%) of benzyl (S). -(4-Cyclopropyl-1- (4- (2- (dimethylamino) ethoxy) indolin-1-yl) -1-oxobutane-2-yl) carbamate was obtained.
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: -0.07-0.09 (2H, m), 0.34-0.46 (2H, m), 0.60-0.73 (1H, m), 1.16-1.43 (2H, m) ), 1.66-1.80 (1H, m), 1.82-1.94 (1H, m), 2.33 (6H, s), 2.72 (2H, t, J = 5.8 Hz), 3.09-3.18 (2H, m), 4.10 ( 2H, t, J = 5.8 Hz), 4.05-4.14 (1H, m), 4.26-4.33 (1H, m), 4.59-4.66 (1H, m), 5.06 (1H, d, J = 12.3 Hz), 5.10 (1H, d, J = 12.3 Hz), 5.61 (1H, J = 9.0 Hz, d), 6.59 (1H, d, J = 8.2 Hz), 7.14 (1H, t, J = 8.2 Hz), 7.10-7.18 (5H, s), 7.81 (1H, d, J = 8.2 Hz).
MS (ESI ⁺ ): 466 [M + H] ⁺

Synthesis of (S) -2-amino-4-cyclopropyl-1- (4- (2-dimethylamino) ethoxy) indolin-1-yl) butane-1-one benzyl (S)-(4-cyclopropyl-) 20% palladium carbon (40) in a solution of 1- (4- (2- (dimethylamino) ethoxy) indolin-1-yl) -1-oxobutane-2-yl) carbamate (178 mg) in methanol (5.0 mL). A suspension of methanol (3.0 mL) of% wet, 33.9 mg) was added, and the mixture was stirred at room temperature and in a hydrogen atmosphere for 1 hour. The reaction mixture was filtered through Celite to obtain (S) -2-amino-4-cyclopropyl-1- (4- (2- (dimethylamino) ethoxy) indoline-1-yl) butane-1-one. The residue concentrated under reduced pressure of the filtrate was used as it was for the synthesis of the compound of Example 6-107 in the next step.
MS (ESI ⁺ ): 332 [M + H] ⁺

<Test Example 1>
G9a Inhibitory Activity Test The G9a inhibitory activity of a compound was evaluated by measuring the enzyme activity of G9a with the Applied Luminescence Evaluation Homogeneous Assay (ALPHA). First, the recombinant human G9a protein (BPS Bioscience, # 51001) was mixed with Tris buffer (50 mM Tris-HCl [pH 9.0], 50 mM NaCl, 0.01% Tween-20, 1 mM DTT) from 0.05 to 0. 7.5 μL diluted to 1 nM and 0.5 μL of the test compound were added to a 384-well microplate (AlphaPlate-384 Shallow Well, PerkinElmer, # 6008359), vortexed and mixed, and then allowed to stand at room temperature for 10 minutes. .. Biotinylated histone H3 peptide (1-21) (AnaSpec, # 61702) 500 nM and SAM (SIGMA, # A7007) 150 μM were premixed 1: 1 and 2 μL was added to each well, mixed with vortex, and then at room temperature. It was allowed to stand for 1 hour. AlphaLISA anti-H3K9me2 acceptor beads (PerkinElmer, # AL117C) and AlphaScreen streptavidin donor beads (PerkinElmer, # 6760002B) the epigenetic buffer (PerkinElmer, AlphaLISA Epigenetics Buffer Kit # AL008C) such that the final concentration after the addition in is 10 [mu] g / ml After diluting each and adding under shading, the mixture was allowed to stand at room temperature for 1 hour. Then, the measurement was performed using an EnSpire Alpha plate reader (PerkinElmer, Waltham, MA, USA). For the G9a inhibitory activity of the test compound, the ratio of the inhibitory rate of the compound was determined when the control value without adding the compound was 0% and the control value without adding the enzyme was 100%, and the G9a enzyme activity was suppressed to 50%. It was calculated compound concentration (IC ₅₀ value) necessary for. The results are shown below.
In the table, IC ₅₀ <50 nM: +++, 50 nM ≦ IC ₅₀ <200 nM: ++, 200 nM ≦ IC ₅₀ : +.

<Test Example 2>
Histone H3K9 dimethylation inhibitory activity test The inhibitory activity of the compound on G9a was evaluated by adding a compound to the human lung cancer cell line NCI-H460 and detecting changes in intracellular histone H3K9 dimethylation level by Western blotting. NCI-H460 cells were cultured in DMEM medium (Fuji Film Wako Pure Chemical Industries, Ltd., 044-29765) containing 10% fetal bovine serum and 4 mM glutamine. The cultured cells were washed with PBS and then exfoliated with trypsin / EDTA, and the cell fluid was adjusted to ^{2.5 × 10 4 cells / mL.} The cell fluid was seeded at 500 μL / well on a 24-well microplate (Thermo Fisher Scientific, 142475) and cultured overnight at _{37 ° C. and 5% CO 2 conditions.} The next day, 0.5 μL / well of the test compound (DMSO solution) was added, and the _{mixture was reacted under 37 ° C. and 5% CO 2} conditions for 72 hours. 0.5 μL / well of DMSO was added to the control wells (DMSO final concentration 0.1%). After removing the medium and washing the cells with PBS, 2 × SDS-PAGE sample buffer (100 mM Tris-HCl (pH 6.8), 4% sodium lauryl sulfate, 2% 2-mercaptoethanol, 20% glycerol, 0.005). % Bromophenol blue) was added in an amount of 50 μL / well to prepare a sample. The collected sample was heated at 95-100 ° C. for 10 minutes and proteins were separated by polyacrylamide gel electrophoresis (SDS-PAGE). The separated protein was then transferred to a polyvinylidene fluoride (PVDF) membrane by a semi-dry blotting method. Anti-dimethylated histone H3K9 antibody diluted 1000-fold with 3% skim milk after immersing the PVDF membrane in 3% skim milk (dissolved in PBS (PBST) containing 0.05% Tween 20) and blocking at room temperature for 30-60 minutes. It was immersed in Abcam, ab1220) and reacted at 4 ° C. overnight. The next day, the PVDF membrane was washed 3 times with PBST, then immersed in HRP (Horseradish peroxidase) -labeled anti-mouse IgG antibody diluted 10000 times with skim milk, and reacted at room temperature for 1 hour. After washing the PVDF membrane with PBST three times, the chemiluminescent substrate solution was immersed in the chemiluminescent HRP substrate (Millipore, WBKLS0500) and allowed to stand at room temperature for 5 minutes, and then left to stand for 5 minutes at room temperature. Lumino Image Analyzer (GE Healthcare, ImageQuant LAS4000) Taken at.
Then, the antibody was stripped from the PVDF membrane using the reprobe reagent EzReprobe (Ato, WSE-7240), and the trimethylated histone H3K9 and histone H3 were detected by the same procedure as described above. For detection, an anti-trimethyl histone H3K9 antibody (39161, diluted 1000-fold) manufactured by Active Motif and an anti-histone H3 antibody (ab1791, diluted 2000-fold) manufactured by Abcam were used. Bands of each protein were quantified from the captured images using image processing software ImageJ (NIH). The ratio of dimethylated histone H3K9 and trimethylated histone H3K9 to histone H3 protein was calculated with the value of the sample to which no compound was added as 100%. Using data analysis software Origin (Lightstone Corp.), the proportion of the dimethylated histone H3K9 was calculated the concentration of the compound is 50% as 50% inhibitory concentration _{(IC 50} value). The results are shown below.
In the table, IC ₅₀ <50 nM: +++, 50 nM ≦ IC ₅₀ <500 nM: ++, 500 nM ≦ IC ₅₀ : +.

<Test Example 3>
Colonization Inhibition Test The colonization inhibition activity of the compound against the human lung cancer cell line NCI-H460 was evaluated. NCI-H460 cells were cultured in DMEM medium (Fuji Film Wako Pure Chemical Industries, Ltd., 044-29765) containing 10% fetal bovine serum and 4 mM glutamine. The cultured cells were washed with PBS and then exfoliated with trypsin / EDTA to prepare a cell fluid having a ^{concentration of 2 × 10 3 cells / mL.} The cell solution was seeded at 1 mL / well on a 12-well microplate (CORNING, 3513), 1 μL / well of the test compound (DMSO solution) was added, and the cells were _{cultured at 37 ° C. under 5% CO 2} conditions for 12 days. The final concentration of DMSO was 0.1%, and 1 μL / well of DMSO was added to the control wells. The medium was discarded every 1 or 2 days, 1 mL / well of fresh medium was added, and 1 μL / well of test compound or DMSO was added. The proportion of colonies formed on the bottom of each well was measured using a fast cell imaging system (Tomy Digital-Biolology, Celigo). The ratio of colonies in each compound-added group was determined by setting the ratio of colonies formed in the wells to which the test compound solution was not added to 1, and the compound concentration (GI ₅₀ ) value required to suppress the colony formation rate to 50% of the control. Was calculated using the data analysis software Origin (LightStone). The results are shown below.
In the table, it is expressed as _{GI 50} <500 nM: +++, 500 nM ≦ GI ₅₀ <1000 nM: ++, 1000 nM ≦ GI _{50: +.}

<Test Example 4>
Globin gene expression test The effect of the obtained compound on the expression level of fetal globin gene on human erythroblast cell line HUDEP-2 was evaluated by quantitative PCR. HUDEP-2 cells in Stemline II hematopoietic stem cell growth medium (Sigma) containing 1 μM dexamethasone (Sigma), 1 μg / ml doxycycline (Sigma), 50 ng / ml recombinant human SCF (R & D SYSTEMS), 3 IU / mL epoetin alfa (Toho Pharmaceutical). It was cultured. A cell solution was prepared so that the cultured cells were 1 × 10 ^{5 cells / mL in a cell culture medium.} Next, the cell solution was seeded on a 6-well plate (VIOLAMO) at a rate of 2 mL / well, 2 μL / well (DMSO final concentration 0.1%) was added to the test compound (DMSO solution), and the temperature was 37 ° C. and 5% CO ₂ conditions. Was cultured for 4 days. As a control, 2 μL / well of DMSO solution was added. Cultured cells were collected by centrifugation at 7500 rpm, 4 ° C. for 5 minutes, and RNA was extracted using Tissue Total RNA Mini Kit (Chiyoda Science). Then, using RiverTra Ace qPCR RT Master Mix (TOYOBO), cDNA was synthesized by reverse transcription reaction at 37 ° C. for 15 minutes and then at 50 ° C. for 5 minutes. Using the diluted cDNA as a template, mix with THUNDERBIRD SYBR qPCR (TOYOBO), and use the CFX Connect Real-Time PCR Detection System (BIORAD) to use the fetal β-globin gene, adult β-globin gene, and GAPDH gene as a reference. Was measured. The primers of the gene used are as follows. Fetal β-globin Forward: 5'-TGGATGATCTCAAGGGCAC-3'; Revase: 5'-TCAGTGGTATTGGAGGACA-3', adult β-globin Forward: 5'-CAGTGGTACGGCTGGCTAC-3'; GAPDH Forward: 5'-GCACCGTCAAGGCTAGGAAC-3'; Revase: 5'-TGGTGAAGACCGCGTGGA-3'. For gene expression analysis, the control to which a 0.1% DMSO solution was added was set to 1, and comparison was performed by the ΔΔCt method.

The compounds according to the present invention include proliferative diseases such as cancer, β-globin disorders, fibrosis, pain, neurodegenerative diseases, Prader-Willi syndrome, malaria, viral infections, myopathy, and autism due to G9a enzyme inhibitory activity. It is useful as a therapeutic agent for diseases or the like or a preventive agent thereof.

Claims

General formula (I):

[In formula (I), R 1 is an oxygen atom, a nitrogen atom or a hydrogen atom;
When R 1 is an oxygen atom or a nitrogen atom, the bond between R 1 and the carbon atom is a double bond;
If R 1 is a hydrogen atom, the bond between R 1 and the carbon atom is a single bond;
R 2 is the following A1), A2) is or A3), * represents a binding position to -CO- in formula (I);

E is an oxygen atom or a hydrogen atom;
If E is an oxygen atom, the bond between E and the carbon atom is a double bond;
If E is a hydrogen atom, the bond between E and the carbon atom is a single bond;
R 2a , R 2b and R 2c are independently hydrogen atoms, C 1 to C 6 alkyl groups, C 2 to C 6 alkenyl groups, halo C 1 to C 6 alkyl groups, C 1 to C 6 alkoxy groups, C. 1 to C 6 alkylamino group, C 1 to C 6 acyl group, C 1 to C 6 alkoxycarbonyl group, C 3 to C 10 cycloalkyl group or hydroxy C 1 to C 6 alkyl group (the C 1 to C 6 alkyl) group, C 2 ~ C 6 alkenyl group, halo C 1 ~ C 6 alkyl group, C 1 ~ C 6 alkoxy group, C 1 ~ C 6 alkylamino group, C 1 ~ C 6 acyl group, C 1 ~ C 6 alkoxy The carbonyl group, C 3 to C 10 cycloalkyl group and hydroxy C 1 to C 6 alkyl group are C 1 to C 6 alkyl group, C 1 to C 6 alkoxy group, C 1 to C 6 alkyl amino group and hydroxy C 1 to it may be one or more substituted with substituents selected from the group consisting of C 6 alkyl group, a linked together with another substituent may form a ring);
R 2b and R 2c may combine with each other to form a ring;
R 2d and R 2e are independently C 1 to C 6 alkyl groups or hydroxy C 1 to C 6 alkyl groups;
R 2d and R 2e may be coupled to each other to form a ring;
R 6 and R 7 are independently hydrogen atoms, C 1 to C 6 alkyl groups, aromatic hydrocarbon ring groups, C 3 to C 10 cycloalkyl groups, 5 to 10 member heteroaryl groups or 3 to 10 member hetero. It is a cycloalkyl group;
R 6 and R 7 may combine with each other to form a ring;
n is 0 or 1;
RingA is an aromatic hydrocarbon ring group, a C 3 to C 10 cycloalkyl group, a 5 to 10 member heteroaryl group or a 3 to 10 member heterocycloalkyl group, which may be substituted with R 8 and R 9, respectively. ;
R 8 is a hydrogen atom, a halogen atom, a cyano group, an amino group, an aminosulfonyl group (-SO 2 NH 2 ), a C 1 to C 6 alkyl group, a halo C 1 to C 6 alkyl group or a C 1 to C 6 alkoxy group. Is;
R 9 is -YZ;
Y is the bond, -O-, -NR 10- or-(CR 11 R 12 ) s- ;
R 10 , R 11 and R 12 are independent hydrogen atoms or C 1 to C 6 alkyl groups, respectively;
s is an integer from 0 to 6;
Z is a hydrogen atom, C 1 to C 6 alkyl group, halo C 1 to C 6 alkyl group, C 1 to C 6 alkoxy group, C 1 to C 6 alkyl amino group, aromatic hydrocarbon ring group, C 3 to. C 10 cycloalkyl group, 5 to 10 member heteroaryl group or 3 to 10 member heterocycloalkyl group (the C 1 to C 6 alkyl group, aromatic hydrocarbon ring group, C 3 to C 10 cycloalkyl group, 5 to The 10-membered heteroaryl group and the 3- to 10-membered heterocycloalkyl group are C 1 to C 6 alkyl groups, halo C 1 to C 6 alkyl groups, C 1 to C 6 alkoxy groups, C 1 to C 6 alkyl amino groups, It may be substituted with one or more substituents selected from the group consisting of C 1 to C 6 acyl groups and C 1 to C 6 alkoxycarbonyl groups);
R 3 is *-(CH 2 ) x- T- (CR 13 R 14 ) y- U, and * indicates the binding position with -CH- in formula (I);
T is binding, -NH-, -O- or -S (O) p- ;
U is hydrogen atom, C 3 ~ C 10 cycloalkyl group or an aromatic hydrocarbon Hajime Tamaki (the aromatic hydrocarbon ring group may be one or more substituted with halogen atom);
R 13 and R 14 are independent hydrogen atoms or C 1 to C 6 alkyl groups, respectively;
x and y are independently integers from 0 to 4;
p is an integer between 0 and 2;
R 4 is a hydrogen atom or a C 1 to C 6 alkyl group;
R 5 is the following B1) or C 1 to C 6 alkyl group, where * indicates the bonding position with -N- in formula (I);

R 15 and R 16 are independently hydrogen atoms, C 1 to C 6 alkyl groups or hydroxy C 1 to C 6 alkyl groups;
R 15 and R 16 may combine with each other to form a ring;
R 15 and R 16 may combine with Ring B to form a ring;
m is 0 or 1;
RingB may be substituted with R 17 , R 18 and R 19 , respectively, aromatic hydrocarbon ring groups, C 3 to C 10 cycloalkyl groups, 5 to 10 member heteroaryl groups or 3 to 10 member heterocycloalkyl groups. Is the basis;
R 17 and R 18 are independently hydrogen atom, halogen atom, hydroxyl group, amino group, cyano group, carbamoyl group (-CONH 2 ), C 1 to C 6 alkyl group, halo C 1 to C 6 alkyl group, hydroxy. C 1 to C 6 alkyl groups, C 1 to C 6 alkoxy groups, C 1 to C 6 alkyl amino groups, C 1 to C 6 alkyl sulfanyl groups, halo C 1 to C 6 alkyl sulfanyl groups, C 1 to C 6 acyls Group, C 1 to C 6 alkoxycarbonyl group, C 1 to C 6 alkylaminocarbonyl group or C 1 to C 6 acylamino group;
R 19 is-(CR 20 R 21 ) r- V- (CR 22 R 23 ) q- Q;
V is a bond, -O-, -NR 24- or -S (O) t- ;
t is an integer between 0 and 2;
R 20 , R 21 , R 22 , R 23 and R 24 are independently hydrogen atoms or C 1 to C 6 alkyl groups;
q and r are independently integers from 0 to 6;
Q is a hydrogen atom, an amino group, a hydroxyl group, a C 1 to C 6 alkyl group, a C 1 to C 6 alkyl amino group, a C 3 to C 10 cycloalkyl group, a 5 to 10 member heteroaryl group or a 3 to 10 member heterocyclo. Alkyl groups (the C 1 to C 6 alkylamino groups, C 3 to C 10 cycloalkyl groups, 5 to 10 member heteroaryl groups and 3 to 10 member heterocycloalkyl groups are halogen atoms, C 1 to C 6 alkyl groups. , C 1 to C 6 alkoxy groups, C 1 to C 6 alkylamino groups, C 1 to C 6 alkoxycarbonyl groups, C 1 to C 6 alkylaminocarbonyl groups and hydroxy C 1 to C 6 alkyl groups. It may be substituted with one or more substituents);
R 17 , R 18 and R 19 may combine with each other to form a ring;
Bonded together R 4 and R 5 may form a ring;
When R 1 is a nitrogen atom, m is 0, and Ring B is a phenyl group that may be substituted with R 17 , R 18 and R 19 , R 1 and the phenyl group combine to form a benzimidazole ring. May]
A compound represented by, or a pharmacologically acceptable salt thereof.
The compound according to claim 1, or a pharmacologically acceptable salt thereof , wherein R 1 is an oxygen atom in the formula (I).
In formula (I), R 2 is the following A1) or A2).

The compound according to claim 2, or a pharmacologically acceptable salt thereof.
In formula (I), R 2 is A2) below;

R 2a is a C 1 to C 6 alkyl group, a C 3 to C 10 cycloalkyl group or a hydroxy C 1 to C 6 alkyl group,
The compound according to claim 3, or a pharmacologically acceptable salt thereof.
In formula (I), R 2 is the following A2b).

The compound according to claim 4, or a pharmacologically acceptable salt thereof.
In formula (I), R 2 is A2b) below;

R 2a is a C 1 to C 6 alkyl group or a C 3 to C 10 cycloalkyl group;
R 2d and R 2e are independently C 1 to C 6 alkyl groups;
R 2d and R 2e may be coupled to each other to form a ring.
The compound according to claim 5, or a pharmacologically acceptable salt thereof.
In formula (I),
R 3 is *-(CH 2 ) x- T- (CR 13 R 14 ) y- U, and * indicates the binding position with -CH- in formula (I);
T is a bond or -S (O) p- ;
U is hydrogen atom, C 3 ~ C 10 cycloalkyl group or an aromatic hydrocarbon Hajime Tamaki (the aromatic hydrocarbon ring group may be one or more substituted with halogen atom);
R 13 and R 14 are independent hydrogen atoms or C 1 to C 6 alkyl groups, respectively;
x and y are independently integers from 0 to 2;
p is 0;
(However, this does not apply when R 3 is a hydrogen atom or a methyl group)
R 5 is the following B1) or C 1 to C 6 alkyl group, where * indicates the bonding position with -N- in formula (I);

RingB may be substituted with R 17 , R 18 and R 19 , respectively, aromatic hydrocarbon ring groups, C 3 to C 10 cycloalkyl groups, 5 to 10 member heteroaryl groups or 3 to 10 member heterocycloalkyl groups. Is the basis;
R 17 and R 18 are independent hydrogen atoms, halogen atoms, hydroxyl groups, amino groups, cyano groups, C 1 to C 6 alkyl groups, halo C 1 to C 6 alkyl groups, hydroxy C 1 to C 6 alkyl groups, respectively. C 1 to C 6 alkoxy groups, C 1 to C 6 alkylamino groups, C 1 to C 6 alkylsulfanyl groups, C 1 to C 6 alkoxycarbonyl groups, C 1 to C 6 alkylaminocarbonyl groups or C 1 to C 6 Acylamino group,
The compound according to claim 6, or a pharmacologically acceptable salt thereof.
In formula (I),
R 3 is a group represented by *-(CH 2 ) x- T- (CR 13 R 14 ) y- U, and * indicates the binding position with -CH- in formula (I);
T is a bond;
U is a hydrogen atom or a C 3 to C 10 cycloalkyl group;
R 13 and R 14 are hydrogen atoms;
x and y are each independently an integer of 1-2;
R 5 is the following B1) or C 1 to C 6 alkyl group, where * indicates the bonding position with -N- in formula (I);

RingB may be substituted with R 17 , R 18 and R 19 , respectively, aromatic hydrocarbon ring groups, C 3 to C 10 cycloalkyl groups, 5 to 10 member heteroaryl groups or 3 to 10 member heterocycloalkyl groups. Is the basis;
R 17 and R 18 are independently hydrogen atoms, halogen atoms, hydroxyl groups, amino groups, cyano groups, C 1 to C 6 alkyl groups, halo C 1 to C 6 alkyl groups, hydroxy C 1 to C 6 alkyl groups or C 1 to C 6 alkoxy groups,
The compound according to claim 7, or a pharmacologically acceptable salt thereof.
In formula (I),
R 2a, R 2d and R 2e are each independently C 1 ~ C 3 alkyl group;
R 3 is an n-butyl group or a 2-cyclopropylethane-1-yl group,
The compound according to claim 8, or a pharmacologically acceptable salt thereof.
In formula (I), R 2 is A1) below;

R 2a , R 2b and R 2c are independently C 1 to C 6 alkyl groups, C 1 to C 6 alkoxycarbonyl groups or C 3 to C 10 cycloalkyl groups;
R 3 is *-(CH 2 ) x- T- (CR 13 R 14 ) y- U, and * indicates the binding position with -CH- in formula (I);
T is a bond;
U is a hydrogen atom or a C 3 to C 10 cycloalkyl group;
R 13 and R 14 are hydrogen atoms;
x and y are independently integers of 1 and 2, respectively.
The compound according to claim 3, or a pharmacologically acceptable salt thereof.
In formula (I), R 2 is A1a) below;

R 2a is a hydrogen atom or a C 1 to C 6 alkyl group;
R 2f is a C 1 to C 6 alkoxy group;
R 2g is a hydrogen atom or a C 1 to C 6 alkoxy group;
R 3 is *-(CH 2 ) x- T- (CR 13 R 14 ) y- U, and * indicates the binding position with -CH- in formula (I);
T is a bond;
U is a hydrogen atom or a C 3 to C 10 cycloalkyl group;
R 13 and R 14 are hydrogen atoms;
x and y are independently integers of 1 and 2, respectively.
The compound according to claim 3, or a pharmacologically acceptable salt thereof.
In formula (I), R 5 is less B1a), * indicates the bonding position with -N- in the formula (I);

G is CH or N;
J is bond, -O- or -NR 25 - and is;
R 25 is a hydrogen atom or a C 1 to C 6 alkyl group;
K is a hydrogen atom, a cyano group, a C 1 to C 6 alkyl group, a halo C 1 to C 6 alkyl group or a 3 to 10 member heterocycloalkyl group (the 3 to 10 member heterocycloalkyl group is C 1 to C 6). It may be substituted with one or more alkyl groups).
The compound according to claim 2, or a pharmacologically acceptable salt thereof.
In formula (I),
R 3 is *-(CH 2 ) x- T- (CR 13 R 14 ) y- U, and * indicates the binding position with -CH- in formula (I);
T is a bond;
U is a hydrogen atom or a C 3 to C 10 cycloalkyl group;
R 13 and R 14 are hydrogen atoms;
x and y are independently integers of 1 and 2, respectively.
R 5 is B1b) below, and * indicates the binding position with -N- in formula (I);

J is bond, -O- or -NR 25 - and is;
R 25 is a hydrogen atom or a C 1 to C 6 alkyl group;
K is a hydrogen atom, a cyano group, a C 1 to C 6 alkyl group, a halo C 1 to C 6 alkyl group or a 3 to 10 member heterocycloalkyl group (the 3 to 10 member heterocycloalkyl group is C 1 to C 6). It may be substituted with one or more alkyl groups).
The compound according to claim 12, or a pharmacologically acceptable salt thereof.
In formula (I), R 5 is less B1c), * indicates the bonding position with -N- in the formula (I);

J is bond, -O- or -NR 25 - and is;
R 25 is a hydrogen atom or a C 1 to C 6 alkyl group;
K is a hydrogen atom, a cyano group, a C 1 to C 6 alkyl group, a halo C 1 to C 6 alkyl group or a 3 to 10 member heterocycloalkyl group (the 3 to 10 member heterocycloalkyl group is C 1 to C 6). It may be substituted with one or more alkyl groups).
The compound according to claim 12, or a pharmacologically acceptable salt thereof.
In formula (I), R 2 is A3) below.

The compound according to claim 14, or a pharmacologically acceptable salt thereof.
In formula (I), R 2 is A3) below;

n is 0;
R 3 is *-(CH 2 ) x- T- (CR 13 R 14 ) y- U, and * indicates the binding position with -CH- in formula (I);
T is a bond;
U is a hydrogen atom or a C 3 to C 10 cycloalkyl group;
R 13 and R 14 are hydrogen atoms;
x and y are independently integers of 1 and 2, respectively.
The compound according to claim 15, or a pharmacologically acceptable salt thereof.
In formula (I), R 2 is A3) below;

n is 0;
RingA is optionally substituted aromatic hydrocarbon ring group by R 8 and R 9,
The compound according to claim 16, or a pharmacologically acceptable salt thereof.
In formula (I);
R 2 is the following A3a);

R 26 is a hydrogen atom or a C 1 to C 6 alkyl group;
R 27 and R 28 are independently hydrogen atoms, C 1 to C 6 alkyl groups or halo C 1 to C 6 alkyl groups, respectively.
The compound according to claim 17, or a pharmacologically acceptable salt thereof.
In formula (I), R 5 is less B1c), * indicates the bonding position with -N- in the formula (I);

J is a bond or -O-;
K is a hydrogen atom or a C 1 to C 6 alkyl group,
The compound according to claim 18, or a pharmacologically acceptable salt thereof.
In formula (I), R 2 is A3) below;

n is 1;
R 3 is *-(CH 2 ) x- T- (CR 13 R 14 ) y- U, and * indicates the binding position with -CH- in formula (I);
T is a bond;
U is a hydrogen atom or a C 3 to C 10 cycloalkyl group;
R 13 and R 14 are hydrogen atoms;
x and y are independently integers of 1 and 2, respectively.
The compound according to claim 15, or a pharmacologically acceptable salt thereof.
In formula (I), R 2 is A3) below;

n is 1;
RingA is an optionally substituted aromatic hydrocarbon ring group by R 8 and R 9;
R 9 is -YZ;
Y is the bond, -O-, -NR 10- or-(CR 11 R 12 ) s- ;
R 10 , R 11 and R 12 are independent hydrogen atoms or C 1 to C 6 alkyl groups, respectively;
s is an integer from 0 to 6;
Z is a hydrogen atom, a C 1 to C 6 alkyl group, a halo C 1 to C 6 alkyl group, a C 1 to C 6 alkoxy group or a C 1 to C 6 alkyl amino group.
The compound according to claim 20, or a pharmacologically acceptable salt thereof.
The compound represented by the general formula (I) is the following formula (II).

The compound according to claim 1, or a pharmacologically acceptable salt thereof.
The compound represented by the general formula (I) is the following formula (II);

In formula (II), R 2 is the following A2b);

R 2a is a C 1 to C 6 alkyl group, a C 3 to C 10 cycloalkyl group or a hydroxy C 1 to C 6 alkyl group;
R 2d and R 2e are independently C 1 to C 6 alkyl groups or hydroxy C 1 to C 6 alkyl groups;
R 2d and R 2e may combine with each other to form a ring;
R 3 is *-(CH 2 ) x- T- (CR 13 R 14 ) y- U, and * indicates the binding position with -CH- in formula (II);
T is a bond;
U is a hydrogen atom or a C 3 to C 10 cycloalkyl group;
R 13 and R 14 are hydrogen atoms;
x and y are independently integers of 1 and 2, respectively.
The compound according to claim 22, or a pharmacologically acceptable salt thereof.
The compound represented by the general formula (I) is the following formula (III);

In formula (III), R 2 is the following A2b);

R 2a , R 2d , and R 2e are independently C 1 to C 3 alkyl groups;
R 3 is *-(CH 2 ) x- T- (CR 13 R 14 ) y- U, and * indicates the binding position with -CH- in formula (III);
T is a bond;
U is a hydrogen atom or a C 3 to C 10 cycloalkyl group;
R 13 and R 14 are hydrogen atoms;
x and y are independently integers of 1 and 2, respectively.
R 5 is below B1), * indicates the bonding position with -N- in the formula (I);

R 15 and R 16 are independent hydrogen atoms or C 1 to C 6 alkyl groups, respectively;
m is 0 or 1;
RingB is an aromatic hydrocarbon ring group or a 5- to 10-membered heteroaryl group, which may be substituted with R 17 , R 18 and R 19, respectively;
R 17 and R 18 are independently hydrogen atoms, cyano groups, C 1 to C 6 alkyl groups or C 1 to C 6 alkoxy groups;
R 19 is-(CR 20 R 21 ) r- V- (CR 22 R 23 ) q- Q;
V is a bond, -O- or -NR 24- ;
R 20 , R 21 , R 22 , R 23 and R 24 are hydrogen atoms;
q and r are independently integers from 0 to 2;
Q is a hydrogen atom, C 1 to C 6 alkylamino group or 3 to 10-membered heterocycloalkyl group (the 3 to 10-membered heterocycloalkyl group is substituted with one or more C 1 to C 6 alkyl groups. May be good);
R 4 and R 5 may be combined with each other to form a ring.
The compound according to claim 1, or a pharmacologically acceptable salt thereof.
Less than,

A compound selected from, or a pharmacologically acceptable salt thereof.
A G9a enzyme-inhibiting composition containing the compound according to any one of claims 1 to 25 or a pharmacologically acceptable salt thereof as an active ingredient.
A pharmaceutical composition containing the compound according to any one of claims 1 to 25 or a pharmacologically acceptable salt thereof as an active ingredient.
Proliferative diseases such as cancer, β-globin dysfunction, fibrosis, pain, neurodegenerative diseases to which the compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof is administered. A method for preventing or treating at least one disease selected from the group of diseases consisting of Prader-Willi syndrome, malaria, viral infections, myopathy, and autism.
At least one disease selected from a group of diseases consisting of proliferative diseases such as cancer, β-globin disorders, fibrosis, pain, neurodegenerative diseases, Prader-Willi syndrome, malaria, viral infections, myopathy, and autism. Use of the compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof for producing a medicament for the prevention or treatment of malaria.
At least one disease selected from a group of diseases consisting of proliferative diseases such as cancer, β-globin disorders, fibrosis, pain, neurodegenerative diseases, Prader Willy syndrome, malaria, viral infections, myopathy, and autism. A pharmaceutical composition containing the compound according to any one of claims 1 to 25 or a pharmacologically acceptable salt thereof and a pharmaceutically acceptable carrier, which is used for the prevention or treatment of.